Alkeneamidocephalosporin esters

ABSTRACT

An oral antibacterial, 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-alkenoylamino]-3-cephem-4-carboxylic acid pharmaceutically acceptable ester represented by the following formula: ##STR1## (wherein R is amino or protected amino, 
     R 1  is straight, branched, or cyclic alkyl optionally substituted by alkoxy, 
     R 2  is hydrogen or a 3-substitutent of cephalosporins, 
     R 3  is a pharmaceutically acceptable ester group, and 
     X is sulfur or sulfinyl).

This invention relates to7beta-[2-(2-amino-4-thiazolyl)-2-alkenoylamino]-3-cephem-4-carboxylicacid pharmaceutically acceptable esters represented by the followingformula: ##STR2## (wherein R is amino or protected amino, R¹ isstraight, branched, or cyclic alkyl optionally substituted by alkoxy,

R² is hydrogen or a 3-substituent of cephalosporins,

R³ is a pharmaceutically acceptable ester group, and

X is sulfur or sulfinyl)

The following explains the variable groups in the formula (I).

The amino protecting group in the protected amino R can be 1C to 8Calkanoyl or substituted alkanoyl (e.g., formyl, acetyl, chloroacetyl,trifluoroacetyl), 7C to 20C aralkyl or substituted aralkyl (e.g.,benzyl, diphenylmethyl, trityl, methoxybenzyl, nitrobenzyl,methylbenzyl), 1C to 8C substituted alkyl (e.g., trichloromethyl,trichloroethyl, tetrahydropyranyl), substituted arylthio, 1C to 8Calkylidene or substituted alkylidene, 7C to 14C aralkylidene orsubstituted aralkylidene (e.g., benzylidene, nitrobenzylidene), acyl [2Cto 12C alkoxycarbonyl or substituted alkoxycarbonyl (in which the alkylpart can be methyl, ethyl, propyl, cyclopropylethyl, isopropyl, butyl,pentyl, hexyl, isobutyl, trichloroethyl, pyridylmethyl, cyclopentyl,cyclohexyl), 8C to 15C aralkoxycarbonyl or substituted aralkoxycarbonyl(in which the aralkyl part can be benzyl, diphenylmethyl, nitrobenzyl),dibasic acid acyl, and the like], trialkylsilyl, trialkylstannyl, acidaddition salt group consisting of an amino group and an acid molecule,and the like which are well known in the art. One or two of theprotecting groups can combine with the amino group.

The alkyl R¹ can preferably be 1C to 8C (especially 1C to 5C) straight,branched, or cyclic alkyl optionally substituted by 1C to 5C alkoxy.Preferably, R¹ is methyl, ethyl, propyl, isopropyl, cyclopropyl,t-butyl, cyclopropylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl,and methoxymethyl.

The 3-substituent of cephalosporins R² can be a well known 3-substituentof cephalosporins, e.g., hydroxy, 1C to 5C alkanoyloxy, halogen, 1C to5C alkoxy, 1C to 5C alkylthio, 1C to 5C alkenylthio, 1C to 5C alkyl, 1Cto 5C alkenyl, heterocyclic thio containing 1 to 4 hetero atom(s)selected from nitrogen, oxygen, or sufur (especially, triazolylthio,tetrazolylthio, oxadiazolylthio, thiadiazolylthio each may have e.g., 1Cto 5C alkyl, alkoxy, substituted methyl), substituted methyl or thelike. Here, the substituent in the said substituted methyl canpreferably be pyridinium, substituted pyridinium, halogen, hydroxy, 1Cto 5C alkoxy, 1C to 5C acyloxy, 1C to 5C alkylthio, 1C to 5Chaloalkylthio, 1C to 5C cyanoalkylthio, heterocyclic thio, or the likeas given above. The substituent on the said substituted alkyl or thelike can preferably be hydroxy, halogen, dimethylamino, carboxy,carbamoyl, etc. Preferably, R² is hydrogen, halogen, methoxymethyl,propoxymethyl, isopropyloxymethyl, propenyloxymethyl,fluoroethoxymethyl, acetoxymethyl, carbamoyloxymethyl,1,2,3-thiadiazol-5-ylthiomethyl,2-methyl-1,3,4-thiadiazol-5-ylthiomethyl,2-amino-1,3,4-thiadiazol-5-ylthiomethyl, or1-(2-hydroxyethyl)tetrazol-5-ylthiomethyl.

The phamaceutically acceptable ester group R³ can be a group showingstrong antibacterial potency on enteral or parenteral administration.Preferably, R³ can be a 2C to 15C ester groups, especially substitutedalkyl ester, for example, straight, branched, cyclic or partially cyclicalkanoyloxyalkyl ester (e.g., acetoxymethyl ester, acetoxyethyl ester,pivaloyloxymethyl ester, pivaloyloxyethyl ester, cyclohexaneacetoxyethylester) or alkoxyformyloxyalkyl ester (e.g., ethoxycarbonyloxyethylester), alkoxyalkyl ester, 2-oxacycloalkyl ester,2-oxo-1,3-dioxolylmethyl ester, (e.g.,4-methyl-2-oxo-1,3-dioxol-5-ylmethyl ester), or the like 1-oxygenated-1Cto 12C-alkyl esters); substituted aralkyl ester (e.g., phenacyl ester,phthalidyl ester); aryl ester (e.g., phenyl ester, tolyl ester, xylylester, indanyl ester); or the like.

Some of the free acids of compound (I) and related compounds are claimedin Japanese Patent Application Kokai No. 57-93982, etc., but nopharmaceutically acceptable ester is disclosed. The present inventorsfound exceedingly high oral availability of the esters and were led tothis invention.

The compounds (I) are antibacterials against aerobic and anaerobicbacteria and are useful as an oral medicine. Especially characteristicfeatures of compounds (I) are antibacterial potency againstGram-positive and Gram-negative bacteria, remarkable oral availability,excretion, distribution, etc. For the prevention or treatment of humaninfections, compound (I) is formulated by a conventional method andadministered usually at a daily dose of 0.1 to 6 g (injection), 0.5 to 5g (oral preparation), or 0.01 to 100 mg (topical or suppositorypreparation). The formulation may contain various additives, otherantibacterials, or the like. Further, compound (I) may be used as astarting material for producing other antibacterials or as a materialfor testing the sensitivity of bacteria. The compound (I) having aprotecting group is also useful as an intermediate for producing thesaid antibacterial compound (I).

Both of the geometric isomers at the double bond in the 7-side chain areantibacterials, but, among them, the isomer having the amido bond and R¹group in cis position is a more potent antibacterial. The trans isomeris also useful as a starting material for producing the cis isomer.

Among the compounds (I), preferable ones from the viewpoint of oralavailability are those having methyl, ethyl, propyl, isopropyl, orcyclopropyl as R¹ , pivaloyloxmethyl, or acetoxymethyl as R³, andpropenyloxymethyl, fluoroethoxymethyl, methoxymethyl, isopropoxymethyl,carbamoyloxymethyl, hydrogen, or chloro as R².

Specific examples of preferable compounds include:

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-(2-propenyl)oxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-(2-fluoroethyl)oxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-methoxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-isopropoxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-butenoylamino]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-butenoylamino]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-cephem-4-carboxylicacid acetoxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-butenoylamino]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-3-cyclopropyl-2-propenoylamino]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-chloro-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-4-methyl-2-pentenoylamino]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-2-hexenoylamino]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester,

7beta-[2-(2-amino-4-thiazolyl)-3-cyclopentyl-2-propenoylamino]-3-cephem-4-carboxylicacid pivaloyloxymethyl ester, and

7beta-[2-(2-amino-4-thiazolyl)-2-pentenoylamino]-3-(1,2,3-thiadiazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester.

The compound (I) having a protecting group is useful also as anintermediate for producing the said antibacterial compound (I).

The compounds of this invention can, for example, be produced asfollows. Generally, protection and deprotection of a functional group(e.g., amino, hydroxy) in compounds (I) can be done conventionallyaccording to a method described in various literature referencesincluding patent publications.

(1) Amidation

The amine (II) or its reactive derivative is reacted with carboxylicacid (III) or its reactive derivative in a conventional manner to givethe objective compound (I) or its derivatives. ##STR3##

A typical reactive derivative of amine (II) have 7-amino activated bysilyl (e.g., trimethylsilyl, methoxydimethylsilyl,t-butyldimethylsilyl), stannyl (e.g.., trimethylstannyl), alkylene (as apart of enamino of the amino with (e.g., aldehyde, acetone,acetylacetone, acetoacetate ester, acetoacetonitrile, acetoacetanilide,cyclopentanedione, acetylbutyrolactone), alkylidene (e.g.,1-haloalkylidenne, 1-haloaralkylidene, 1-alkoxyalkylidene,1-alkoxyaralkylidene, 1-alkoxy-1-phenoxyalkylidene, alkylidene,aralkylidene), acid (as a salt of the amino with, e.g., mineral acid,carboxylic acid, sulfonic acid), easily removable acyl (e.g., alkanoyl),or the like and that protected at other functions of the molecule.

Carboxylic acid (III) is used in the presence of a condensing reagent[carbodiimide (e.g., N,N'-diethylcarbodiimide,N,N'-dicyclohexylcarbodiimide, carbonyl compound (e.g.,carbonyldiimidazole), isoxazolinium salt, acylamino compound (e.g.,2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), or the like]. Thereactive derivative includes acid anhydride (e.g., symmetric anhydride,mixed anhydride [with a mineral acid (e.g., phosphoric acid, sulfuricacid, carbonic half ester), organic acid (e.g., alkanoic acid,aralkanoic acid, sulfonic acid)], intramolecular acid anhydride (e.g.,isocyanate, ketene), acid halide (i.e., a mixed anhydride of the acidwith hydrogen halide), acid halide, reactive ester [enol ester (e.g.,vinyl ester, isopropenyl ester), aryl ester (e.g., phenyl ester,halophenyl ester, nitrophenyl ester), heterocyclic ester (e.g., pyridylester, 1-hydroxybenzotriazolyl ester), ester with N-hydroxy compound,diacylhydroxylamine ester (ester with e.g., N-hydroxysuccinimide,N-hydroxyphthalimide), thiol ester (e.g., aralkylthiol ester,heterocyclic thiol ester), or the like], reactive amide [e.g., aromaticamide (e.g., amide with imidazole, triazole,2-ethoxy-1,2-di-hydroquinoline), diacylanilide], and the like. The acidscavenger to be used with the said reactive derivatives include aninorganic base (e.g., oxide, hydroxide, carbonate, hydrogen carbonate,or the like or alkali metal, alkaline earth metal), organic base (e.g.,tertiary amine, aromatic base,), oxirane (e.g., alkylene oxide,aralkylene oxide), pyridinium salt (e.g., tripyridiniumtriazinetrichloride), adsorbent (e.g., Celite), and the like.

(2) Introduction of the 3-substituent

Compound (I) but having a leaving group-substituted methyl at position 3is treated with a hetero aromatic thiol, aromatic base, or reactivederivative thereof giving objective compound (I). Halogen, sulfonyloxy,alkanoyloxy, dihaloacetoxy, trihaloacetoxy, and the like are the typicalleaving groups. An alkali metal salt, ammonium salt, carboxylate ester,and the like are typical reactive derivatives of the thiol. The reactionproceeds at 0° C. to 60° C. even in an anhydrous or aqueous solvent.This reaction is promoted by a dehydrating reagent, phosphorylchlorides, thiocyanates, or the like.

Compound (I) having alkanoyloxymethyl or carbamoyloxymethyl at position3 is prepared from compound (I) but having hydroxymethyl at position 3and protected carboxy at position 4 by treating with a reactivederivative of alkanoic acid or N-protected carbamic acid, and ifrequired, deprotected at the stage where the objective group can remainin the target compound.

Compound (I) having no carbon atom attached to position 3 can beprepared by the reaction of 3-(hydroxy or oxo)-compound (if required,after activation by acylation, halogenation, or the like) with anucleophilic reagent, etc. to give a 3-nucleophilic group substitutedcompound; or by elimination reaction of 3-(hydroxy, acyloxy, orhalo)cepham compound by heat or with base; reduction of a 3-(acyloxy orhalo)-3-cephem compound giving 3-unsubstituted compound; or the likeeach in a conventional method.

(3) Isomerization at position 7 side chain

Each geometric isomer of Compound (I) can be transformed into the other.This reaction is taken place by the action of acid, base or light. Here,the said acid includes a mineral acid (e.g., hydrochloric acid, sulfuricacid, phosphoric acid), carboxylic acid (e.g., formic acid,trifluoroacetic acid), sulfonic acid (e.g., methanesulfonic acid,benzenesulfonic acid), etc.; the said base includes an inorganic base(e.g., sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate), strong organic base (e.g., triethylamine, potassiumt-butoxide, DBU), etc.

(4) Esterification of carboxy

The carboxy group at position 4 can be esterified by a known method, forexample, (a) A reaction of an alkali metal salt of the carboxylic acidwith a halide, sulfonate, or the like of the ester group in the presenceof an acid scavenger. (b) A reaction of the carboxylic acid or itsreactive derivative with alcohol having the ester group in the presenceof a condensing reagent. (c) A reaction of the carboxylic acid with adiazo compound having the ester group.

(5) Introduction of an amino-protecting group

When Compound (I) has amino in its molecule, the amino can be protectedby using, for example, as follows: (a) an alkoxycarbonyl,aralkoxycarbonyl, alkanoyl, etc., group is introduced by reacting 1 to 5molar equivalents of halide, symmetric anhydride, or mixed anhydride ofthese groups in the presence of an acid scavenger at -30° to 50° C.; (b)an alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, arylsulfenyl, aralkyl,trialkylsilyl, trialkylstannyl, etc., group is introduced by reacting 1to 5 molar equivalents of halide of the group in the presence of 1 to 10molar equivalents of an acid scavenger in a solvent at -30° to 100° C.for 1 to 10 hours; (c) a tetrahydropyranyl, tetrahydrofuranyl, etc.,group is introduced by the reaction with dihydropyran, dihydrofuran,etc., in a solvent for 1 to 10 hours. (d) a trialkylsilyl group isintroduced by the reaction with a derivative of disilazane, acetamido,or the like (e.g., hexamethyldisilazane, bistrimethylsilylacetamide), ina conventional manner.

(6) Deprotection of protected amino as R

A protected amino group in compound (I) can be deprotected, for example,by the following convetional methods: (a) an alkoxycarbonyl group (e.g.,tert-butoxycarbonyl), can be deprotected by reacting with an acid, forexample, a strong acid (e.g., trifluoroacetic acid,trifluoromethanesulfonic acid), or Lewis acid (e.g., aluminum chloride,tin chloride, titanium chloride, zinc chloride), if required in thepresence of a cation scavenger (e.g., anisole, benzenethiol); (b) anaralkoxycarbonyl group (e.g., carbobenzoxy, methylcarbobenzoxy,diphenylmethoxycarbonyl) or the like amino protecting group can bedeprotected by reacting with a Lewis acid and a cation scavenger asgiven above; (c) a lower alkanoyl group (e.g., formyl, acetyl,chloroacetyl), Schiff base forming group, i.e., a divalent carbon group(e.g., ethylidene, propylidene, benzylidene, substituted benzilidene),aralkyl (e.g., trityl, substituted trityl), arylthio (e.g.,phenylsulfenyl), tetrahydropyranyl, silyl or stannyl (e.g.,trimethylstannyl, trimethylsilyl), and other ones are deprotected byreacting with acid (e.g., hydrochloric acid, sulfuric acid,methanesulfonic acid); and (d) some protecting group has its specificmethod for deprotection (e.g., the reaction of thiourea orN-alkyldithiocarbamate for haloacetyl, hydrazine for a dibasic acidacyl, and phosphorus pentachloride and alkanol for amide).

(7) Sulfoxide formation

Compound (I) having sulfide group is oxidized, for example, by thefollowing conventional methods. In this case, when the starting materialhas 2-double bond, the latter migrates to the position 3. (a) peracid(an industrially available per-mineral acid, percarboxylic acid,persulfonic acid, etc.); (b) ozone; (c) hydrogen peroxide; and (d)peroxide (e.g., boron peroxide, nickel peroxide, sodium peroxide, ureaperoxide) preferably in an inert solvent (e.g., halohydrocarbon, ester,water) to give the corresponding sulfoxide (I). These reactions may beaccelerated with (e.g., phosphoric acid, polyphosphoric acid, phosphoricacid monoester, alkanoic acid, acid salts of Group VII atoms in thePeriodic Table, e.g., tungstates). The reaction is preferably carriedout with 1 to 2 molar equivalents of an oxidizing reagent at 0° to 35°C. for 1 to 20 hours.

(8) Reduction of the sulfoxide

When compound (I) has sulfinyl in the molecule (e.g., when X is SO), itcan be reduced by a conventional method to give the correspondingsulfide (I), for example, with 2 to 5 molar equivalents of a reducingreagent (e.g., trivalent phosphorus compund, stannous salt, iodide) inan inert solvent (e.g., dimethylformamide, dichloromethane, dioxane) at-20° to 50° C. for 2 to 50 hours.

(9) Reaction conditions

The reactions from (1) to (8) are usually carried out at -30° C. to 100°C. (preferably at -20° C. to 50° C.) for 10 minutes to 10 hours in asolvent, if required in a dry condition. Other conventional conditionsmay be applied to the reactions.

The typical reaction solvent can be a hydrocarbon (e.g., pentane,hexane, octane, benzene, toluene, xylene), halohydrocarbon (e.g.,dichloromethane, chloroform, carbon tetrachloride, dichloroethane,trichloroethane, chlorobenzene), ether (e.g., diethyl ether, methylisobutyl ether, dioxane, tetrahydrofuran), ketone (e.g., acetone, methylethyl ketone, cyclohexanone), ester (e.g., ethyl acetate, isobutylacetate, methyl benzoate), nitrohydrocarbon (e.g., nitromethane,nitrobenzene), nitrile (e.g., acetonitrile, benzonitrile), amide (e.g.,formamide, acetamide, dimethylformamide, dimethylacetamide,hexamethylphosphorotriamide), sulfoxide (e.g., dimethyl sulfoxide),carboxylic acid (e.g., formic acid, acetic acid, propionic acid),organic base (e.g., diethylamine, triethylamine, pyridine, picoline,collidine, quinoline), alcohol (e.g., methanol, ethanol, propanol,hexanol, octanol, benzyl alcohol), water, or other industrial solvent ora mixture of two or more of these.

(10) Work up

The objective products are recovered from the reaction mixture byremoving a contaminant (e.g., unreacted starting materials, by-products,solvents) by a conventional method (e.g., extraction, evaporation,washing, concentration, precipitation, filtration, drying), and by acombination of conventional purification (e.g., adsorption, elution,distillation, precipitation, separation, chromatography).

(11) Examples

The following examples illustrate the embodiment of this invention. Thephysical constants of the products are listed on the tables. In thetables, IR shows cm⁻¹ values and NMR shows delta values in ppm and Jvalues showing coupling constants in Hz values.

In Tables 1 and 2, all compounds have R¹ and amido groups in cispositions.

In the exampls, "part" shows weight per weight of starting beta-lactamsand "molar equivalent" shows mole number per starting beta-lactams.

Work-up of the examples are done usually (if required after adding asolvent e.g., water, acid, dichloromethane) and the separated organiclayer is washed with water, dried, and vacuum-distilled giving residuewhich may be purified conventionally (e.g., by chromatography oversilica gel, crystallization, precipitation).

EXAMPLE 1

A 7beta-amino compound (2) (1 equivalent) is treated with carboxylicacid corresponding to the 7beta-side chain (3) or its reactivederivative to give the corresponding amide (1), for example, by anacylation represented by the following equation and as exemplifiedbelow: ##STR4##

(1) In a mixture of dichloromethane (30 volumes), cyanuric chloride (1.1equivalents), pyridine (4 equivalents), and carboxylic acid (3) (1.1equivalents), stirred for 5 minutes to 2 hours at -30° C. to 10° C.

(2) In a mixture of dichloromethane (3 volumes), phosphorus oxychloride(1.1 equivalents), triethylamine (1.5 equivalents), and carboxylic acid(3) (1.1 equivalents), stirred for 20 minutes to 2 hours at -10° C. to10° C.

(3) In a mixture of chloroform (3 volumes), toluene (1 volume), picoline(2 equivalents), oxalyl chloride (1 equivalent), and carboxylic acid (3)(1.1 equivalents), stirred for 10 minutes to 2 hours at -50° C. to 10°C.

(4) To a solution of2-(2-t-butoxycarbonylcarbonylaminothiazol-4-yl)-2-pentenoic acid (149mg), triethylamine (83 microliter) in dichloromethane (5 ml) is addedmethanesulfonyl chloride (0.04 ml) at -60° C. After stirring at the sametemperature for 2 hours, a solution of 7beta-amino-3-cephem-4-carboxylicacid 1-acetoxyethyl ester (161 mg) and N-methylmorpholine (0.132 ml) indichloromethane is added dropwise to the reaction mixture. The mixtureis stirred at -60° to -10° C. for 3 hours, diluted with hydrochloricacid, and separated to obtain organic layer. The layer is washed withwater, dried, and purified by column chromatography to give7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid 1-acetoxyethyl ester (470 mg).

(5) In a manner similar to that of above (1) to (4), the compoundslisted on Table 2 are prepared.

EXAMPLE 2 (Amino deprotection)

(1) To a solution of a tertiary butoxycarbonylamino compound of Table 2in dichloromethane (0.3 to 3 parts) are added tri-fluoroacetic acid (0.3to 3 parts) and anisole (0.5 to 5 parts). The mixture is stirred at -10°to 40° C. for 10 minutes to 3 hours. The reaction mixture isconcentrated to remove the solvent and reagents, and the resultingresidue is washed with benzene or ether to give the corresponding aminocompound in Table 1. Yield: 70 to 80%.

(2) To a solution of a chloroacetamido compound on Table 2 in a mixtureof tetrahydrofuran (15 parts) and methanol (15 parts) are added thioureaor N-methyldithiocarbamate ester (4 equivalents) and sodium acetate (2equivalents), and the mixture is kept at room temperature overnight. Themixture is concentrated, diluted with ethyl acetate, washed with water,dried, and concentrated to give the corresponding amino compound onTable 1.

(3) To a solution of a formamido or Schiff base compound of Table 2 informic acid, acetic acid, or ethanol (10 parts) is added 1 to3N-hydrochloric acid (0.1 to 3 parts), and the mixture is stirred atroom temperature for 1 to 3 hours. The reaction mixture is concentrated,diluted with dichloromethane, washed with aqueous sodium hydrogencarbonate and water, dried, and concentrated to give the correspondingamino compound on Table 1.

(4) To a solution of a formylamino, tertiary butoxycarbonylamino, orbenzyloxycarbonylamino compound on Table 2 in dichloromethane (5 to 9parts) are added anisole (2 to 8 parts) and aluminum chloride, titaniumtetrachloride, or tin tetrachloride (1 to 3 equivalents), and themixture is stirred at -35° to 10° C. for 10 minutes to 24 hours. Thereaction mixture is extracted with diluted hydrochloric acid. Theextract solution is passed through a column of adsorbent to removesalts, and eluate is concentrated to give the corresponding aminocompound on Table 1.

(5) A solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-butenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester (160 mg) in trifluoroacetic acid (2 ml) isstirred at room temperature for 120 minutes and concentrated. To theresulting residue is added aqueous sodium hydrogen carbonate andextracted with ethyl acetate. The extract solution is purified by silicagel chromatography to give7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-butenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester (75 mg).

(6) In a manner similar to above (1) to (5), amino compounds on Table 1are synthesized from the corresponding protected amino compounds.

EXAMPLE 3 (Esterification) (pivaloyloxymethyl ester)

(1) To a solution of a potassium salt of a carboxylic acid inN,N-dimethylformamide (2 to 5 parts) is added iodomethyl pivalate (1 to2 equivalents) at -50 to room temperature. After stirring for 15 minutesto 2 hours, the mixture is diluted with ethyl acetate, washed with icewater and aqueous sodium hydrogen carbonate, dried, and concentrated.The residue is crystallized from ethyl acetate to give thepivaloyloxymethyl ester. This pivaloyloxymethyl ester (250 mg), cornstarch (150 mg), and magnesium stearate (5 mg) are mixed, granulated,and encapsulated in a conventional manner. This capsule (2 to 3capsules) is given orally thrice a day to treat a patient suffering froman infection caused by Escherichia coli.

In a similar manner, pivaloyloxymethyl compounds listed on Table 2 areprepared.

(acetoxymethyl ester)

(2) In place of iodomethyl pivalate of above (1), bromomethyl acetate isused under the same condition to give the corresponding acetoxyethylester.

In a similar manner, acetoxymethyl compounds listed on Table 2 areprepared.

(acetoxyethyl ester)

(3) In place of iodomethyl pivalate of above (1), bromoethyl acetate isused under the same condition to give the corresponding acetoxyethylester.

In a similar manner, acetoxyethyl compounds listed on Table 2 areprepared.

(1-pivaloyloxyethyl ester)

(4) To a soultion of7beta-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-pentenoylamino]-3-cephem-4-carboxylicacid (240 mg) in N,N-dimethylformamide (2.4 ml) is added potassiumcarbonate (138 mg) at -25° to 30° C. and the mixture is stirred forseveral minutes. To the mixture is added pivaloyloxyethyl iodide (480microliter) and the mixture is stirred for 60 minutes. The reactionmixture is diluted with ethyl acetate, washed with aqueous saline andsodium hydrogen carbonate, and water, dried and concentrated. Theresidue is chromatographed over silica gel to give the correspondingpivaloyloxyethyl ester (161 mg). Yield. 53%.

In a similar manner, pivaloyloxyethyl esters listed on Table 2 areprepared.

(ethoxycarbonyloxyethyl ester)

(5) To a solution of7beta-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-pentenoylamino]-3-cephem-4-carboxylicacid (240 mg) in N,N-dimethylformamide (2.4 ml) is added potassiumcarbonate (138 mg) and 1-ethoxycarbonyloxyethyl bromide (150 mg) at -10°C. After stirring for 30 minutes, the mixture is diluted with ethylacetate, washed with aqueous saline and sodium hydrogen carbonate, andwater, dried and concentrated. The residue is chromatographed oversilica gel to give the corresponding ethoxycarbonyloxyethyl ester (191mg). Yield. 64.1%.

In a similar manner, ethoxycarbonyloxyethyl esters listed on Table 2 areprepared.

(5-methyl-2-oxo-1,3-dioxol-3-en-4-ylmethyl ester)

(6) A mixture of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid (144 mg), potassium carbonate (83 mg), and dimethylformamide (3 ml)is stirred for 40 minutes at room temperature and mixed with4-bromomethyl-5-methyl-1,3-dioxol-4-en-2-one (102 mg) indimethylformamide (1 ml). After stirring at 0° C. for 30 minutes, themixture is diluted with aqueous hydrochloric acid and extracted withethyl acetate. The extract is purified by silica gel chromatography togive7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid 5-methyl-2-oxo-1,3-dioxol-4-en-4-ylmethyl ester (83 mg) as paleyellow powder.

(cyclohexaneacetoxyethyl ester)

(7) To a solution of7beta-[2-(2-t-butoxycarbonylamino-4-thiazolyl)-2-pentenoylamino]-3-cephem-4-carboxylicacid (240 mg) in N,N-dimethylformamide (2.4 ml) is added potassiumcarbonate (138 mg) and 1-cyclohexaneacetoxyethyl iodide (355 mg) at -10°C. After stirring for 45 minutes, the mixture is diluted with ethylacetate, washed with aqueous saline and sodium hydrogen carbonate, andwater, dried and concentrated. The residue is chromatographed oversilica gel to give the corresponding cyclohexaneacetoxyethyl ester (152mg).

In a similar manner, cyclohexaneacetoxyethyl esters listed on Table 2are prepared.

(8) In a manner similar to above, pharmacological esters on Table 2 canbe prepared from the corresponding carboxylic acid.

EXAMPLE 4 (Sulfoxide formation)

(1) A sulfide is stirred with aqueous 30% hydrogen peroxide (1equivalent) in a mixture of phosphoric acid (1 equivalent),dichloromethane (17 parts), and methanol (1 part) under ice cooling for10 minutes to give the corresponding sulfoxide.

(2) To a solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-chloro-2-cephem-4-carboxylicacid pivaloyloxymethyl ester (410 mg) in dichloromethane (3 ml) is addeddropwise a solution of m-chloroperbenzoic acid (47.4 mg) indichloromethane (1 ml) with stirring at 0° C. After stirring at the sametemperature for 20 minutes, the reaction mixture is diluted with aqueoussodium hydrogen carbonate. The organic layer is separated, washed withwater, dried, and concentrated. The resulting residue is purified bysilica gel column chromatography to give7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-chloro-3-cephem-4-carboxylicacid 1-oxide pivaloyloxymethyl ester (135 mg) as crystals.

EXAMPLE 5 (Sulfoxide reduction)

(1) to a solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-penteoyl]amino-3-cephen-4-carboxylicacid 1-oxide pivaloyloxymethyl ester (61 mg) in dichloromethane (2 ml)is added phosphorus tribromide (19.3 microliter) at -30° C. and themixture is stirred for 30 minutes. The reaction mixture is diluted withaqueous sodium hydrogen carbonate. The organic layer is separated,washed with water, dried, and concentrated. The residue is purified bysilica gel column chromatography to give7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid pivaloyloxymethyl ester (51 mg).

(2) In the reaction condition of above 1), phosphorus tribromide indichloromethane at -30° C. for 30 minutes is substituted by potassiumiodide (6 molar equivalents) in acetone (11 parts) for 1 hour under icecooling or acetyl chloride (13 equivalents) and stannous chloride (2.5molar equivalents) in N,N-dimethylformamide (12 parts) under ice coolingfor 21 hours to give the same sulfide.

(3) In a manner similar to above, sulfides on Table 1 or Table 2 can beprepared by reducing the corresponding sulfoxides.

EXAMPLE 6 (Acid addition salt)

(1) [trifluoroacetate] A solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester (450 mg) in trifluoroacetic acid (5 ml) isstirred at room temperature for 120 minutes and then concentrated. Theresidue is diluted with aqueous sodium hydrogen carbonate and extractedwith ethyl acetate. The extract is purified by silica gel chromatographyto give the corresponding free amine. This is dissolved indichloromethane (4 ml), mixed with trifluoroacetic acid (1 ml), andvacuum-concentrated. The crystalline residue is triturated in a mixtureof ether and petroleum ether to give7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid pivaloyloxymethyl ester trifluoroacetate (290 mg).

(2) [Hydrochloride] A solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid pivaloyloxymethyl ester (360 mg) in a mixture of anisole (2 ml) andtrifluoroacetic acid (2 ml) is stirred at room temperature for 150minutes and concentrated. The residue is dissolved in aqueous sodiumhydrogen carbonate and extracted with ethyl acetate. The extract ispurified by silica gel column chromatography to give7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid pivaloyloxymethyl ester (250 mg). This is dissolved indichloromethane, mixed with a solution of hydrochloric acid in ethylacetate, and concentrated. The crystalline residue is washed with etherto give the hydrochloride of above ester.

(3) In a manner similar to above, acid addition salts can be preparedfrom the corresponding amino compounds on Table 1.

EXAMPLE 7

(1) To a solution of aminothiazolyl compound in dichloromethane is addedformic acid and acetic anhydride, chloroacetyl chloride and pyridine, ornitrobenzaldehyde and toluenesulfonic acid, and the mixture is stirredat -30 to room temperature for 1 to 3 hours. The mixture is treated in ausual manner to give the corresponding amino-protected compound as shownon Table 4.

Preparation 1

To a solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid 1-oxide diphenylmethyl ester (265 mg) in a mixture of anisole (0.8ml) and dichloromethane (1.5 ml) is added trifluoroacetic acid (1 ml) at0° C. with stirring. After 45 minutes' stirring, the mixture isconcentrated in vacuum. The residue is washed with petroleum ether andether to give7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-cephem-4-carboxylicacid 1-oxide (180 mg).

NMR (CDCl₃ -OD₃ CD)δ: 1.11(t, J=7.5 Hz, 3H), 1.55(s, 9H), 2.49(quintet,J=7.5 Hz, 2H), 4.78(d, J=4.5 Hz, 1H), 6.13(d, J=4.5 Hz, 1H), 6.40(m,1H), 6.45(t, J=7.5 Hz, 1H), 6.79(s, 1H).

Preparation 2

To a solution of 2-amino-1,3,4-thiadiazole-5-thiol (156 mg) indimethylformamide (3 ml) is added a solution (0.3 ml) of 5.2N-sodiummethoxide in methanol with stirring at 0° C. to give the sodium salt.After neutralizing excess sodium methoxide with dry ice, a solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-bromomethyl-3-cephem-4-carboxylicacid 1-oxide diphenylmethyl ester (590 mg) in dimethylformamide (2 ml)is added to the mixture. After stirring at 0° C. for 30 minutes, thereaction mixture is poured into ice water and extracted with ethylacetate to give crude7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-(2-amino-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid 1-oxide diphenylmethyl ester in a quantitative yield.

NMR (CDCl₃)δ: 1.07(t, J=8 Hz, 3H), 1.48(s, 9H), 2.52(quintet, J=8 Hz,2H), 3.61, 3.82(ABq, J=18 Hz, 2H), 4.60, 3.70(ABq, J=18 Hz, 2H), 4.55(d,J=5 Hz, 1H), 5.60(brs, 2H), 6.15(dd, J=5 Hz, J=9 Hz, 1H), 6.40(t, J=8Hz, 1H), 6.74(s, 1H), 6.88(s, 1H), 7.20˜7.45(m, 10H), 8.83(d, J=9 Hz,1H).

The ester group of this product is removed in a manner similar to thatof Preparation 1 and the sulfoxide is reduced in a manner similar tothat of Example 5-2) to give7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-(2-amino-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid.

Preparation 3

(1) To a mixture of 2-(2-t-butoxycarbonylaminothiazol-4-yl)-pentenoicacid (75 mg), triethylamine (0.041 ml), and dichloromethane (3 ml) isadded dropwise methanesulfonyl chloride (0.02 ml) at -60° C. withstirring. After stirring at the same temperature for 5 hours, a solutionof 7beta-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic aciddiphenylmethyl ester p-toluenesulphonate salt (153 mg) andN-methylmorpholine (0.05 ml) in dichloromethane (3 ml) is added dropwiseto the mixture. After stirring for 3.5 hours, the mixture is quenchedwith diluted hydrochloric acid. The organic layer is separated, washedwith water, dried, and concentrated. The residue is purified by silicagel column chromatography to give7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid diphenylmethyl ester (155 mg).

IR (CHCl₃)ν: 3430, 1785, 1726, 1672, 1543, 1326, 1158, 980.

NMR (CDCl₃)δ: 1.10(t, J=7.5 Hz, 3H), 1.51(s, 9H), 2.55(quintet, J=7.5Hz, 2H), 3.16(s, 2H), 4.80, 4.97(ABq, J=14.4 Hz, 2H), 4.82(s, 2H),4.93(d, J=4.5 Hz, 1H), 5.67(dd, J=4.5 Hz, J=8 Hz, 1H), 6.37(t, J=7.5 Hz,1H), 6.68(s, 1H), 6.80(s, 1H), 7.22˜7.40(m, 10H), 7.82(d, J=8 Hz, 1H),10.0(brs, 1H).

(2) To an ice cold solution of7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid diphenylmethyl ester (855 mg), anisole (3.3 ml), anddichloromethane (8.3 ml) is added trifluoroacetic acid (1.93 ml) withstirring. After reacting at the same temperature for 30 minutes, themixture is concentrated in vacuum. The residue is washed with petroleumether and ether to give pale brown7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (640 mg).

IR (CHCl₃)ν: 3425, 3360br, 1778, 1725, 1700, 1660, 1327, 1258, 1160,1078.

NMR (CDCl₃ -CD₃ OD)δ: 1.07(t, J=7.5 Hz, 3H), 1.53(s, 9H), 2.41(quintet,J=7.5 Hz, 2H), 3.43, 3.61(ABq, J=19.8 Hz, 2H), 4.87, 5.10(ABq, J=14.4Hz, 2H), 5.08(d, J=5.0 Hz, 1H), 5.85(d, J=5.0 Hz, 1H), 6.41(t, J=7.5 Hz,1H), 6.80(s, 1H).

Experiment

Male rats weighing 20 to 25 gram are freely fed an aqueous solution of40% glucose and vitamins instead of a chow diet for one day. Next day, asuspension of amoxicillin (the reference compound) or one of the esters(the test compounds) in aqueous 5% arabic gum having a potency of 2 mgper milliliter was orally administered at a dose of 40 mg/kg each of thereference compound or the test compounds. Then, the blood is taken at 15minutes intervals to determine the activity in the plasma. For thedetermination is used Escherichia coli for esters and Micrococcus luteusfor amoxicillin by the agar plate dispersion method. The results arelisted on the following table.

                  TABLE                                                           ______________________________________                                        Maximum plasma level (gamma/ml) of Compound (I)                               (in which R is amino and R.sup.3 = pivaloyloxymethyl)                         after oral administration to mice                                                                          maximum serum                                    No.     R.sup.1  R.sup.2     level                                            ______________________________________                                        1       Me       H           8.6                                              2       Me       CH.sub.2 OCONH.sub.2                                                                      13.4                                             3       Et       H           14.1                                             4       Et       CH.sub.2 OCONH.sub.2                                                                      9.3                                              amoxicillin          15.7                                                     ______________________________________                                    

    TABLE 1      Physical constants of pharmaceutical esters      ##STR5##      No. R R.sup.1 R.sup.2 R.sup.3 X IR: ν (CHCl.sub.3) cm.sup.-1 NMR:     δ      (CDCl.sub.3) ppm Example No                                         1     H.sub.2 N Me H POM S   nd. 1.21(s, 9H), 1.93(d, J=7Hz, 3H), 3.40(dd, A     of ABX, J=5Hz, J= (2-1),(2-4)        18.9Hz, 1H), 3.60(dd, B of ABX,     J=3Hz, J=18.9Hz, 1H), 5.03(d, J=        5Hz, 1H), 5.80, 5.91(ABq, J=6Hz,     2H), 5.96(dd, J=5Hz, J=8Hz,        1H), 6.25(s, 1H), 6.49(q, J=7Hz, 1H),     6.59(dd, X of ABX, J=3Hz,        J=5Hz, 1H), 8.40(d, J=8Hz, 1H).  2     H.sub.2 N Me CH.sub.2 OCONH.sub.2 POM S 3550, 3485, 3430, 1.21(s, 9H),     1.90(d, J=7.0Hz, 3H), 3.40, 3.52(ABq, J=18.0Hz, (2-5)       3395, 1786,     1735, 2H), 4.76, 5.03(ABq, J=16.9Hz, 2H), 5.02(d, J=5.0Hz, 1H), 5.12       1672, 1525, 1330, (s, 2H), 5.54(brs, 2H), 5.77˜5.95(m, 3H),     6.22(s, 1H), 6.45(q,       1126. J=7.0Hz, 1H), 8.45(d, J=9.0Hz, 1H).  3     H.sub.2 N Me CH.sub.2 S(1,2,3-thiadiazol-5-yl) POM S 3480, 3390, 1785,     1.20(s, 9H), 1.95(d, J=8Hz, 3H), 3.51, 3.62(Abq, J=15Hz, 2H), (2-1)      1750, 1670, 1600, 4.06, 4.16(ABq, J=14Hz, 2H), 5.08(d, J=5Hz, 1H),     5.50(brs, 2H),       1520, 1365, 1110, 5.83(s, 2H), 5.92(dd, J=5Hz,     J=8Hz, 1H), 6.28(s, 1H), 6.52(q, J=       990. 8Hz, 1H), 8.53(s, 1H),     8.63(d, J=8Hz, 1H).  4 H.sub.2 N Et H AOM S   nd 1.05(t, J=8Hz, 3H),     2.11(s, 3H), 2.37(quintet, J=8Hz, 2H), 3.23˜ (2-1)        3.77(m,     2H), 5.02(d, J=5Hz, 1H), 5.26(s, 2H), 5.82, 5.92(ABq, J=        6Hz,     2H), 5.98(dd, J=5Hz, J=9Hz, 1H), 6.32(s, 1H), 6.42(t, J=8        Hz,     1H), 6.56˜6.66(m, 1H), 8.10(d, J=9Hz, 1H).  5 H.sub.2 N Et H AOE S       nd 1.05(t, J=8.0Hz, 3H), 1.54(d, J=6.0Hz, 3H), 2.07(s, 3H), 2.36     (2-1),(3-3)        (quintet, J=8.0Hz, 2H), 3.42(dd, A of ABX, J=7.0Hz,     J=20.0Hz,        1H), 3.61(dd, B of ABX, J=4.0Hz, J=20.0Hz, 1H), 5.03(d,     J=5.0Hz,        1H), 5.46(brs, 2H), 5.98(dd, J=5.0Hz, J=9.0Hz, 1H),     6.29(s, 1H),        6.42(t, J=8.0Hz, 1H), 6.58(dd, X of ABX, J=4.0Hz,     J=7.0Hz, 1H),        6.99(q, J=6.0Hz, 1H), 8.19(d, J=9.0Hz, 1/2H),     8.26(d, J=9.0Hz,        1/2H).  6 H.sub.2 N Et H POM S 3475, 3380, 3325,     1.02(t, J= 7.5Hz, 3H), 1.20(s, 9H), 2.34(dq, J=7.5Hz, J=8Hz, 2H),     (2-1),(2-2),       1783, 1750, 1674, 3.43(dd, A of ABX, J=7Hz, J=18.9Hz,     1H), 3.63(dd, B of ABX, J= (2-3),(2-4),       1522, 1285, 1123, 3Hz,     J=18.9Hz, 1H), 5.06(d, J=5Hz, 1H), 5.48(s, 2H), 5.84, 5.94 (3-1),(5-2)         982. (ABq, J=5.4Hz, 2H), 5.97(dd, J=5Hz, J=8Hz, 1H), 6.27(s, 1H),         6.42(t, J=8Hz, 1H), 6.63(dd, X of ABX, J=3Hz, J=7Hz, 1H), 8.36      (d, J=8Hz, 1H).  7 H.sub.2 NHCl Et H POM S 3250, 2715br, 1.12(t,     J=7.5Hz, 3H), 1.20(S, 9H), 2.37(quintet, J=7Hz, 2H), (6-2)       1782,     1747, 1660, 3.75(dd, A of ABX, J=7Hz, J=19.8Hz, 1H), 3.71(dd, B of ABX,     J=       1627, 1278, 1123, 3.5Hz, J=19.8Hz, 1H), 5.17(d, J=5Hz, 1H),     5.82, 5.91(ABq, J=6.3       982. Hz, 2H), 5.92(d, J=5Hz, 1H), 6.32(t,     J=7.5Hz, 1H), 6.67(dd, X        of ABX, J=3.5Hz, J=7.5Hz, 1H), 6.69(s,     1H).  8 H.sub.2 N Et H POE S   nd 1.06(t, J=8Hz, 3H), 1.20(s, 9H),     1.53(d, J=5Hz, 3H), 2.38(quint- (2-1)        et, J=8Hz, 2H), 3.20˜3     .76(m, 2H), 5.02(d, J=5Hz, 1H), 5.23(brs,        2H), 5.87˜6.06(m,     1H), 6.33(s, 1H), 6.42(t, J=8Hz, 1H), 6.52˜        6.62(m, 1H),     6.86˜7.00(m, 1H), 7.96, 8.06(2Xd, J=9Hz, 1H).  9 H.sub.2 N Et H     ECE S   nd 1.05(t, J=8Hz, 3H), 1.30(t, J=7Hz, 3H), 1.57(d, J=5Hz, 3H),     2.37 (2-1)        (quintet, J=8Hz, 2H), 3.20˜3.80(m, 2H), 4.20(q,     J=7Hz, 2H), 5.01        (d, J=5Hz, 1H), 5.23(brs, 2H), 5.96(dd, J=5Hz,     J=9Hz, 1H), 6.33        (s, 1H), 6.42(t, J=8Hz, 1H), 6.53˜6.63(m,     1H), 6.80˜7.00(m, 1H),        7.95(d, J=9Hz, 1H). 10 H.sub.2 N Et     H DOL S 3480, 3385, 3325 1.05(t, J=7.5Hz, 3H), 2.19(s, 3H), 2.38(quintet,      J=7.5Hz, 2H), (2-1)       1816, 1781, 1732, 3.43(dd, A of ABX, J=6.0Hz,     19.8Hz, 1H), 3.70(dd, B of ABX, J=       1676, 1523, 1282, 4.0Hz,     J=19.8Hz, 1H), 4.95, 5.13(ABq, J=14Hz, 2H), 5.09(d, J=5       1015. Hz,     1H), 5.49(brs, 2H), 6.01(dd, J=5Hz, J=8.5Hz, 1H), 6.30(s,        1H),     6.44(t, J=7.5Hz, 1H), 6.63(dd, X of ABX, J=4Hz, J=6Hz,        1H),     8.35(d, J=8.5Hz, 1H). 11 H.sub.2 N Et H CHAE S   nd 0.85˜1.90(m,     11H), 1.06(t, J=8Hz, 3H), 1.53(d, J=5Hz, 3H), 2.20 (2-1)        (d,     J=6Hz, 2H), 2.38(quintet, J=8Hz, 2H), 3.20˜3.76(m, 2H), 5.02      (d, J=5Hz, 1H), 5.25(brs, 2H), 5.96(dd, J=5Hz, J=9Hz, 1H), 6.32     (s, 1H), 6.42(t, J=8Hz, 1H), 6.53˜6.63(m, 1H), 6.97(q, J=5Hz,       1H), 8.00, 8.05(2Xd, J=9Hz, 1H). 12 H.sub.2 N Et Cl POM S 3470, 3385,     3330, 1.05(t, J=7.5Hz, 3H), 1.22(s, 9H), 2.40(quintet, J=7.5Hz, 2H),     (2-1),(5-2)       1783, 1756, 1670, 3.51, 3.82(ABq, J=18.0Hz, 2H),     5.12(d, J=5.0Hz, 1H), 5.27(bs,       1602, 1523, 1122, 2H), 5.83˜6.     01(m, 3H), 6.32(s, 1H), 6.41(t, J=7.5Hz, 1H), 8.27       1103, 985. (d,     J=8.0Hz, 1H). 13 H.sub.2 N Et Cl POM SO 3490, 3375, 1805, 1.06(t,     J=7.5Hz, 3H), 1.22(s, 9H), 2.47(quintet, J=7.5Hz, 2H), (2-1)       1775,     1677, 1601, 3.65, 3.87(ABq, J=18.0Hz, 2H), 4.66(d, J=5Hz, 1H), 5.47(brs,           1120, 987. 2H), 5.86, 5.99(ABq, J=6Hz, 2H), 6.17(dd, J=5Hz,     J=10Hz, 1H),        6.38(s, 1H), 6.38(t, J=7.5Hz, 1H), 8.42(d, J=10Hz,     1H). 14 H.sub.2 N Et CH.sub.2 OCH.sub.3 POM S 3480, 3390, 2960, 1.06(t,     J=8Hz, 3H), 1.22(s, 9H), 2.40(quintet, J=8Hz, 2H), 3.32 (2-1),(2-5)      1785, 1750, 1670, (s, 3H), 3.56(s, 2H), 4.30(s, 2H), 5.06(d, J=5Hz,     1H), 5.23(brs,       1600, 1520, 1360, 2H), 5.90(s, 2H), 5.95(dd, J=5Hz,     J=9Hz, 1H), 6.35(s, 1H), 6.45       1125, 1095. (t, J=8Hz, 1H), 8.06(d,     J=9Hz, 1H). 15 H.sub.2 N Et CH.sub.2 Oi-Pr POM S 3470, 3370, 2950,     1.06(t, J=8Hz, 3H), 1.15(d, J=5Hz, 6H), 1.22(s, 9H), 2.37(quint- (2-1)         1775, 1740, 1670, et, J=8Hz, 2H), 3.57(s, 2H), 3.58(septet, J=5Hz,     1H), 4.35(s,       1595, 1360, 1115. 2H), 5.04(d, J=5Hz, 1H), 5.29(brs,     2H), 5.87(s, 2H), 5.92(dd, J=       5Hz, J=9Hz, 1H), 6.32(s, 1H),     6.43(t, J=8Hz, 1H), 8.07(d, J=9Hz,        1H). 16 H.sub.2 N Et CH.sub.2     O(2-propenyl) POM S 3480, 3390, 1785, 1.03(t, J=7Hz, 3H), 1.20(s, 9H),     2.17˜2.52(m, 2H), 3.59(s, 2H), (2-1)       1750, 1675, 1600.     3.97(m, 2H), 4.38(s, 2H), 5.08(d, J=5Hz, 1H), 5.13˜5.36(m, 2H),         5.52(brs, 2H), 5.69˜6.11(m, 4H), 6.28(s, 1H), 6.43(t, J=7Hz,          1H), 8.37(d, J=8Hz, 1H). 17 H.sub.2 N Et CH.sub.2 O(2-fluoroethyl)     POM S 3485, 3396, 1785, 1.05(t, J=8Hz, 3H), 1.23(s, 9H), 2.38(dq, J=8Hz,     J=8Hz, 2H), (2-1)       1752, 1676, 1602, 3.56(s, 2H), 3.66(dt, J=4.5Hz,     J=28.8Hz, 2H), 4.40(s, 2H), 4.50       1124. (dt, J=4.5Hz, J=46.8Hz,     2H), 5.03(d, J=5Hz, 1H), 5.19(s, 2H),        5.85(s, 2H), 5.92(dd,     J=5Hz, J=8.5Hz, 1H), 6.32(s, 1H), 6.41(t,        J=8Hz, 1H), 8.02(d,     J=8.5Hz, 1H). 18 H.sub.2 N Et CH.sub.2 OCOMe POM S 3470, 3380, 1785,     1.05(t, J=8.0Hz, 3H), 1.22(s, 9H), 2.07(s, 3H), 2.88(quintet, J= (2-1)         1742, 1670, 1602, 8.0Hz, 2H), 3.42, 3.61(ABq, J=18.0Hz, 2H), 4.82,     5.12(ABq, J=       1521, 1122. 13.5Hz, 2H), 5.09(d, J=4.5Hz, 1H),     5.45(brs, 2H), 5.86, 5.95        (ABq, J=6.0Hz, 2H), 5.95(dd, J=4.5Hz,     J=8.0Hz, 1H), 6.31(s, 1H),        6.44(t, J=8.0Hz, 1H), 8.31(d, J=8.0Hz,     1H). 19 H.sub.2 N Et CH.sub.2 OCONH.sub.2 AOE S 3480, 3390, 1780,     1.05(t, J= 7.5Hz, 3H), 1.53(d, J=6.0Hz, 3H), 2.07(s, 3H), 2.41 (2-1)       1727, 1668, 1500, (quintet, J=7.5Hz, 2H), 3.38, 3.55(ABq, J=15.0Hz,     2H), 4.78       1325, 1070. 5.02(ABq, J=13.5Hz, 2/2H), 4.81, 5.05(ABq,     J=13.5Hz, 2/2H), 4.99        (s, 2H), 5.01(d, J=5.0Hz, 1H), 5.30(brs,     2H), 5.92(dd, J=5.0Hz,        J=9.0Hz, 1H), 6.34(s, 1H), 6.38(t,     J=7.5Hz, 1H), 6.96(q, J=6.0        Hz, 1/2H), 7.08(q, J=6.0Hz, 1/2H),     7.94(d, J=9.0Hz, 1/2H), 7.96        (d, J=9.0Hz, 1/2H). 20 H.sub.2 N Et     CH.sub.2 OCONH.sub.2 POM S   nd 1.05(t, J=8.0Hz, 3H), 1.23(s, 9H),     2.38(quintet, J=8.0Hz, 2H), (2-1)        3.44, 3.68(ABq, J=18.9Hz, 2H),     4.82, 5.08(ABq, J=14.4Hz, 2H),        5.05(d, J=5.0Hz, 1H), 5.14(s, 2H),     5.51(s, 2H), 5.83˜6.02(m,        3H), 6.34(s, 1H), 6.41(t,     J=8.0Hz, 1H), 8.17(d, J=8.5Hz, 1H). 21 H.sub.3 N.sup.+CF.sub.3 COO  Et     CH.sub.2 OCONH.sub.2 POM S Anal. Calculated for C.sub.25 H.sub.30     N.sub.5 O.sub.10 S.sub.2 F.sub.3 : C, 44.05; H, 4.44; N, 10.28; F, 8.36.     (6-1)        Found: C, 44.10; H, 4.62; N,  9.89; F, 8.40. 22 H.sub.2 N     Et CH.sub.2 OCONH.sub.2 POE S 3480, 3390, 2960, 1.08(t, J=8Hz, 3H),     1.20(s, 9H), 1.54(d, J=5Hz, 3H), 2.35(quint- (2-1)       1785, 1740,     1670, et, J=8Hz, 2H), 3.44, 3.58(ABq, J=18Hz, 2H), 4.80, 5.02(ABq, J=        1390, 1330, 1065. 15Hz, 2H), 5.06(d, J=5Hz, 1H), 5.87, 5.92(2Xd,     J=5Hz, 1H), 6.36        (s, 1H), 6.36(t, J=8Hz, 1H), 6.93, 7.02(2Xq,     J=5Hz, 1H). [CDCl.sub.3 +        CD.sub.3 OD] 23 H.sub.2 N Et CH.sub.2     OCONH.sub.2 ECE S   nd 1.06(t, J=7Hz, 3H), 1.30(t, J=7Hz, 3H), 1.56(d,     J=6Hz, 3H), 2.35 (2-1)        (quintet, J=7Hz, 2H), 3.50(brs, 2H),     4.22(q, J=7Hz, 2H), 4.82        5.04(ABq, J=15Hz, 2H), 5.03, 5.06(2Xd,     J=5Hz, 1H), 5.86, 5.90        (2Xd, J=5Hz, 1H), 6.36(s, 1H), 6.36(t,     J=7Hz, 1H), 6.86, 6.97(2Xq,       J=6Hz, 1H). [CDCl.sub.3 +CD.sub.3 OD]     24 H.sub.2 N Et CH.sub.2 OCONH.sub.2 DOL S 3320br, 1820, 1.07(t,     J=8.0Hz, 3H), 2.17(s, 3H), 2.35(quintet, J=8.0Hz, 2H), (2-1),(2-4)     1775, 1726, 1660, 3.43, 3.58(ABq, J=18.9Hz, 2H), 4.72, 5.06(ABqmJ=13.5Hz,      2H),       1330, 1077. 5.01(s, 2H), 5.05(d, J=5Hz, 1H), 5.89(d, J=5Hz,     1H), 6.33(s,        1H), 6.35(t, J=8Hz, 1H). 25 H.sub.2 N Et CH.sub.2     S(1,2,3-thiadiazol-5-yl) POM S 3475, 3390, 2960, 1.06(t, J=8Hz, 3H),     1.20(s, 9H), 2.43(quintet, J=8Hz, 2H), 3.56 (2-1)       1790, 1750,     1670, (s, 2H), 4.00, 4.20(ABq, J=13Hz, 2H), 5.04(d, J=5Hz, 1H), 5.36       1600, 1360, 1110. (brs, 2H), 5.81(s, 2H), 5.91(dd, J= 5Hz, J=9Hz, 1H),     6.34(s, 1H),        6.40(t, J=8Hz, 1H), 8.16(d, J=9Hz, 1H), 8.52(s, 1H).     26 H.sub.2 N Et CH.sub.2 S(1,2,3-thiadiazol-5-yl) ECE S 3436, 3336,     1762, 1.06(t, J=7Hz, 3H), 1.32(t, J=7Hz, 3H), 1.54(d, J=6Hz, 3H), 2.42     (2-1)       1663, 1619, 1529, (quintet, J=7Hz, 2H), 3.54(brs, 2H), 4.06,     4.16(Abq, J=13Hz,       1373, 1269, 1243, 2H),4.23(q, J=7Hz, 2H),     5.01(d, J=5Hz, 1H), 5.46(brs, 2H), 5.90       1074, 995, 867. (dd,     J=5Hz, J=8Hz, 1H), 6.33(s, 1H), 6.38(t, J=7Hz, 1H), 6.84(q,       [KBr]     J=6Hz, 1H), 8.18(d, J=8Hz, 1H), 8.50(s, 1H). 27 H.sub.2 N Et CH.sub.2     S(2-Me1,3,4-thiadiazol-5-yl) POM S 3440, 3340, 3210, 1.03(t, J=8Hz, 3H),     1.20(s, 9H), 2.36(quintet, J=8Hz, 2H), 2.70 (2-5)       2980, 1785,     1750, (s, 3H), 3.70(s, 2H), 4.17, 4.62(ABq, J=14Hz, 2H), 5.02(d, J=5       1665, 1620, 1530. Hz, 1H), 5.86, 5.93(ABq, J=5Hz, 2H), 5.90(dd, J=5Hz,     J=9Hz, 1H).       [KBr] 6.31(s, 1H), 6.39(t, J=8Hz, 1H), 8.13(d, J=9Hz,     1H). 28 H.sub.2 N Et CH.sub.2 S(2-H.sub.2 N1,3,4-thiadiazol-5-yl) POM S     3430, 3340, 3190, 1.07(t, J=8Hz, 3H), 1.20(s, 9H), 2.35(quintet, J=8Hz,     2H), 3.65 (2-5)       2980, 1775, 1745, (brs, 2H), 4.06, 4.23(ABq,     J=13Hz, 2H), 5.05(d, J=5Hz, 1H),        1660, 1615, 1520. 5.75˜5.92     (m, 3H), 6.35(t, J=8Hz, 1H), 6.35(s, 1H) [CDCl.sub.3 -CD.sub.3 OD].      [KBr] 29 H.sub.2 N Et CH.sub.2 S(1-HOCH.sub.2 CH.sub.2tetrazol-5-yl)     POM S 3400, 2970, 1790, 1.07(t, J=8Hz, 3H), 1.23(s, 9H), 2.37(quintet,     J=8Hz, 2H), 3.73 (2-1)       1750, 1675, 1620, (s, 2H), 3.86˜4.06(m     , 2H), 4.25˜4.53(m, 4H), 5.08(d, J=5Hz, 1H),       1610, 1530.     5.83˜5.98(m, 3H), 6.37(s, 1H), 6.37(t, J=8Hz, 1H) [CDCl.sub.3     -CD.sub.3 OD]. 30 H.sub.2 N n-Pr H POM S 3480, 3390, 1790, 0.92(t,     J=7Hz, 3H), 1.21(s, 9H), 1.47(brq, J=7Hz, 2H), 2.30(brq, (2-1)     1750, 1675, 1640, J=7˜8Hz, 2H), 3.23˜3.78(m, 2H), 5.05(d,     J=5Hz, 1H), 5.60(brs,       1600. 2H), 5.82, 5.93(ABq, J=5Hz, 2H),     5.95(dd, J=8Hz, J=5Hz, 1H),       6.37(s, 1H), 6.41(t, J=8Hz, 1H),     6.56˜6.65(m, 1H), 8.23(d, J=8        Hz, 1H). 31 H.sub.2 N i-Pr H     POM S 3480, 3390, 1780, 1.06(d, J=7Hz, 6H), 1.22(s, 9H), 2.73˜3.13(     m, 1H), 3.22˜3.77(m, (2-1)       1740, 1670, 1635, 2H), 5.00(d,     J=5Hz, 1H), 5.43(brs. 2H), 5.81, 5.90(ABq, J=5Hz,       1600. 2H),     5.96(dd, J=8Hz, J=5Hz, 1H), 6.22(d, J=11Hz, 1H), 6.37(s,        1H),     6.53˜6.73(m, 1H), 7.57(d, J=8Hz, 1H). 32 H.sub.2 N cyc-Pr H POM S     3480, 3390, 1784, 0.5˜1.03(m, 4H), 1.20(s, 9H), 2.0˜2.5(m,     1H), 3.42(dd, J=7Hz, J= (2-1)       1745, 1664, 1600, 19.8Hz, (A of     ABX), 1H), 3.60(dd, J=3Hz, J=19.8Hz, (B of ABX),       1122. 1H),     5.03(d, J=5Hz, 1H). 5.30(brs, 2H), 5.80(d, J=11Hz, 1H),        5.84,     5.93(ABq, J=5.4Hz, 2H), 6.03(dd, J=5Hz, J=9Hz, 1H), 6.33        (s, 1H),     6.61(dd, J=3Hz, J=7Hz, (X of ABX), 1H), 8.06(d, J=9Hz,        1H). 33     H.sub.2 N t-Bu H POM S 3480, 3390, 1788, 1.18(s, 9H), 1.21(s, 9H),     3.45(dd, A of ABX, J=6.0Hz, J=20.0Hz, (2-1), (2-4)       1745, 1678,     1496, 1H), 3.52(dd, B of ABX, J=4.0Hz, J=20.0Hz, 1H), 5.0(d, J=4.5Hz,        1123. 1H), 5.18(brs, 2H), 5.80, 5.88(ABq, J=5.5Hz, 2H), 5.98(dd, J=          4.5Hz, J=8.5Hz, 1H), 6.33(s, 1H), 6.41(s1H), 6.56(dd, J=4.0Hz,       J=6.0Hz, 1H), 6.74(d, J=8.5Hz, 1H). 34 H.sub.2 N cyc-PrMe H POM S     3485, 3390, 1784, 0.1˜1.3(m, 5H), 1.22(s, 9H), 2.30(dd, J=7.5Hz,     J=7.5Hz, 2H), (2-1)       1746, 1672, 1601, 3.44(dd, J=7Hz, J=19Hz, (A     of ABX), 1H), 3.64(dd, J=4Hz, J=19Hz,       1128. (B of ABX), 1H),     5.06(d, J=5Hz, 1H), 5.31(brs, 2H), 5.36, 5.46        (ABq, J=5.5Hz, 2H),     6.00(dd, J=5Hz, J=8.5Hz, 1H), 6.38(s, 1H),        6.55(t, J=7.5Hz, 1H),     6.65(dd, J=4Hz, J=7Hz, (X of ABX), 1H),        8.14(d, J=8.5Hz, 1H). 35     H.sub.2      N cyc-Pn H POM S 3478, 3385, 1786, 1.22(s, 9H), 1.3˜2.13(m, 8H),     2.75˜3.20(m, 1H), 3.39(dd, J=6.3 (3-1)       1746, 1670, 1601, Hz,     J=19.8Hz, (A of ABX), 1H), 3.58(dd, J=2.7Hz, J=19.8Hz, (B of       1112.     ABX), 1H), 5.02(d, J=5Hz, 1H), 5.37(brs, 2H), 5.82, 5.94(ABq, J=     7Hz, 2H), 6.00(dd, J=5Hz, J=8.5Hz, 1H), 6.35(d, J=10Hz, 1H),     6.38(s, 1H), 6.60(dd, J=2.7Hz, J=8.5Hz, (X of ABX), 1H), 7.96        (d,     J=8.5Hz, 1H). 36 H.sub.2 N cyc-PnMe H POM S 3495, 3395, 1797, 1.23(s,     9H), 1.40˜1.92(m, 9H), 2.39(dd, J=7.5Hz, J=7.5Hz, 2H), (2-1)     1756, 1678, 1602, 3.04(dd, J=6.3Hz, J=19Hz, (A of ABX), 1H), 3.62(dd,     J=3.6Hz, J=       1132. 19Hz, (B of ABX), 1H), 5.02(d, J=5.5Hz, 1H),     5.22(brs, 2H),        5.82, 5.92(ABq, J=5.5Hz, 2H), 5.98(dd, J=5.5Hz,     J=8.5Hz, 1H),        6.33(s, 1H), 6.45(t, J=7.5Hz, 1H), 6.60(dd,     J=3.6Hz, J=6.3Hz, (X        of ABX), 1H), 7.85(d, J=8.5Hz, 1H). 37     H.sub.2 N cyc-Pn CH.sub.2 OCONH.sub.2 POM S 3480, 3400, 1783, 1.21(s,     9H), 1.40˜2.0(m, 8H), 2.75˜3.12(m, 1H), 3.42, 3.52(ABq,     (2-1)       1740, 1668, 1601, J=19.8Hz, 2H), 4.76, 5.01(ABq, J=14.4Hz,     2H), 4.98(d, J=5Hz,       1122. 1H), 5.28(brs, 2H), 5.55(brs, 2H), 5.82,     5.88(ABq, J=6.3Hz, 2H),        5.90(dd, J=5Hz, J=8.5Hz, 1H), 6.28(d,     J=9.5Hz, 1H), 6.34(s, 1H),        7.68(d, J=8.5Hz, 1H). 38 H.sub.2 N     MeOMe CH.sub.2 OCONH.sub.2 POM S 3490, 3431, 3396, 1.22(s, 9H), 3.36(s,     3H), 3.42, 3.59(ABq, J=18Hz, 2H), 4.39(d, (2-1)       3202, 3189, 1785,     J=5.5Hz, 2H), 4.85(brs, 2H), 4.94, 5.23(ABq, J=14Hz, 2H), 5.02     1735, 1668, 1602, (d, J=4.5Hz, 1H), 5.90(m, 3H), 6.51(s, 1H), 6.56(t,     J=5.5Hz,       1325, 1123, 1097, 1H), 8.87(d, J=9Hz, 1H).       1072,     1000, 982     (Abbreviations)     Ac = acetyl, AOE = acetoxyethyl, AOM = acetoxymethyl, BOC =     tbutoxycarbonyl, br = broad, Bu = butyl, Cbz = benzyloxycarbonyl, CHAE =     cyclohexylacetoxyethyl, CPBA = chloroperbenzoic acid, cyc = cyclo, DCM =     dichloromethane, DMA = dimethylacetamide, DMF = dimethylformamide, DOL =     4methyl-2-oxo-1,3-dioxol-5-ylmethyl, ECE = ethoxycarbonyloxyethyl, Et =     ethyl, Me = methyl, nd = not done, POE = pivaloyloxyethyl, POM =     pivaloyloxymethyl, Pr = propyl, TFA = trifluoroacetic acid, Yld = yield.

    TABLE 2      Physical constants of protected pharmaceutical esters      ##STR6##       No R R.sup.1 R.sup.2 R.sup.3 X IR: ν(CHCl.sub.3) cm.sup.-1 NMR:     δ(CDCl.sub.3) ppm Example No        1 BOCNH Me H POM S 3415, 3100br; 1.20(s, 9H), 1.51(s, 9H), 2.04(d,     J=7Hz, 3H), 3.42(dd, A of ABX; (3-1), (1-3)       1786, 1746, 1725,     J=5Hz, J=9.9Hz, 1H), 3.61(dd, B of ABX, J=3Hz, J=9.9Hz, 1H),       1678,     1545, 1280, 5.02(d, J=5Hz, 1H), 5.85(s, 2H), 5.94(dd, J=5Hz, J=8Hz, 1H),           1155. 6.42˜6.62(m, 2H), 6.69(s, 1H), 8.01(d, J=8Hz, 1H);     9.62(brs;        1H).  2 BOCNH Me CH.sub.2 OCONH.sub.2 POM S 3550, 3415,     1787, 1.21(s, 9H), 1.51(s, 9H), 2.02(d, J=7.0Hz, 3H), 3.39, 4.13(ABq,     (3-1)       1730, 1678, 1545, J=17.0Hz, 2H), 4.81, 5.05(ABq, J=13.5Hz,     2H), 5.02(d, J=4.5Hz,       1300, 1155. 1H), 5.05(s, 2H), 5.87(s, 2H),     5.91(dd, J=4.5Hz, J=8.5Hz, 1H),        6.52(q, J=7.0Hz, 1H), 6.73(s,     1H), 7.90(d, J=8.5Hz, 1H), 8.47        (brs, 1H).  3 BOCNH Me CH.sub.2     S(1,2,3-thiadiazol-5-yl) POM S 3420, 2975, 1795, 1.20(s, 9H), 1.50(s,     9H), 2.06(d, J=7Hz, 3H), 3.54(brs, 2H), (3-1)       1755, 1730, 1680,     3.96, 4.18(ABq, J=13Hz, 2H), 5.03(d, J=5Hz, 1H), 5.80(s, 2H),     1550, 1375, 1300, 5.86(dd, J=5Hz, J=8Hz, 1H), 6.52(q, J=7Hz, 1H),     6.72(s, 1H),       1160, 1115, 995. 8.15(d, J=8Hz, 1H), 8.52(s, 1H),     9.05(brs, 1H).  4 BOCNH Et H AOM S 3410, 2960, 1785, 1.07(t, J=8Hz, 3H),     1.53(s, 9H), 2.10(s, 3H), 2.46(quintet, J=8 (3-2)       1720, 1670,     1540, Hz, 2H), 3.20˜3.76(m, 2H), 4.99(d, J=5Hz, 1H), 5.82,     5.88(ABq,       1370, 1285, 1155, J=6Hz, 2H), 5.95(dd, J=5Hz, J=9Hz,     1H), 6.43(t, J=8Hz, 1H), 6.53˜       1005. 6.63(m, 1H), 6.75(s,     1H), 7.75(d, J=9Hz, 1H), 8.76(brs, 1H).  5 BOCNH Et H AOE S   nd 1.07(t,     J=7.5Hz, 3H), 1.53(s, 9H), 1.53(d, J=6.0Hz, 3H), 2.07(s, (1-2), (3-3)         3H), 2.48(quintet, J=7.5Hz, 2/2H), 2.50(quintet, J=7.5Hz, 2/2H),        3.21˜3.75(m, 2H), 4.94(d, J=4.5Hz, 1/2H), 4.99(d, J=4.5Hz,       1/2H), 5.79˜6.02(m, 1H). 6.42(t, J=7.5Hz, 1H), 6.49˜6.61(m,      1H),        6.74(s, 1H), 6.93(q, J=6.0Hz, 1/2H), 6.99(q, J=6.0Hz,     1/2H),        7.70(d, J=8.5Hz, 1/2H), 7.74(d, J=8.5Hz, 1/2H), 8.60(brs,     1/2H),        9.55(brs, 1/2H).  6 BOCNH Et H POM S   nd 1.06(t, J=8Hz,     3H), 1.19(s, 9H), 1.52(s, 9H), 2.44(quintet, J= (3-1), (5-1)        8Hz,     2H), 3.43(dd, A of ABX, J=7Hz, J=19.8Hz, 1H), 3.61(dd, B        of ABX,     J=4Hz, J=19.8Hz, 1H), 5.03(d, J=5Hz, 1H), 5.83, 5.90        (ABq,     J=4.5Hz, 2H), 5.97(dd, J=5Hz, J=8Hz, 1H), 6.45(t, J=8Hz,        1H),     6.58(dd, X of ABX, J=4Hz, J=7Hz, 1H), 6.73(s, 1H), 7.88(d,        J=8Hz,     1H), 8.94(brs, 1H).  7 BOCNH Et H POM SO 3405, 3185br, 1.08(t, J=7.5Hz,     3H), 1.21(s, 9H), 1.52(s, 9H), 2.52(quintet, J= (3-1), (4-1)       1802,     1751, 1720, 7.5Hz, 2H), 3.28(dd, A of ABX, J=1.5Hz, J=19.8Hz, 1H),     3.82(dd,       1670, 1545, 1155. B of ABX, J=6.0Hz, 19.8Hz, 1H),     4.59(dd, J=1.5Hz, J=4.5Hz, 1H),        5.84, 5.96(ABq, J=7Hz, 2H),     6.23(dd, J=4.5Hz, J=9Hz, 1H), 6.38        (dd, X of ABX, J=1.5Hz, J=6Hz,     1H), 6.47(t, J=7.5Hz, 1H), 6.72        (s, 1H), 8.81(brs, 1H), 8.94(d,     J=9Hz, 1H).  8 BOCNH Et H POE S 3410, 1785, 1740, 1.08(t, J=8Hz, 3H),     1.20(s, 9H), 1.53(s, 9H), 1.53(d, J=5Hz, (3-4)       1726, 1675, 1545,     3H), 2.25˜2.65(m, 2H), 3.20˜3.80(m, 2H), 4.97, 5.02(2Xd,     J=5Hz,       1290, 1155, 1070. 1H), 5.95(dd, J=5Hz, J=9Hz, 1H), 6.40(t,     J=8Hz, 1H), 6.49˜6.59        (m, 1H), 6.74(s, 1H), 6.90, 6.96(2Xq,     J=7Hz, 1H), 7.40, 7.45(2X        d, J=9Hz, 1H).  9 BOCNH Et H ECE S     3420, 2960, 1785, 1.07(t, J=7Hz, 3H), 1.30(t, J=7Hz, 3H), 1.53(s, 9H),     1.56(d, J=5 (3-5)       1765, 1730, 1675, Hz, 3H), 2.30˜2.66(m,     2H), 3.10˜3.80(m, 2H), 4.20(q. J=7Hz, 2H),       1550, 1370, 1290,     4.94, 5.00(2Xd, J=5Hz, 1H), 5.85, 5.95(2Xdd, J=5Hz, J=9Hz, 1H),     1155, 1080 6.43(t, J=7Hz, 1H), 6.46˜6.63(m, 1H), 6.73(s, 1H),     6.84, 6.90(2X        q, J=5Hz, 1H), 7.72(d, J=9Hz, 1H). 10 BOCNH Et H     DOL S 3408, 3220br, 1.07(t, J=7.5Hz, 3H), 1.52(s, 9H), 2.17(s, 3H),     2.96(quintet, J= (3-6)       1818, 1783, 1725, 7.5Hz, 2H), 3.40(dd, A of     ABX, J=7.0Hz, J=19.0Hz, 1H), 3.62(dd,       1722, 1670, 1523, B of ABX,     J=3.0Hz, J=19.0Hz, 1H), 4.97(s, 2H), 5.00(d, J=5.0       1288, 1153. Hz,     1H), 5.94(dd, J=5.0Hz, J=9.0Hz, 1H), 6.43(t, J=7.5Hz, 1H),     6.56(dd, X of ABX, J=3.0Hz, J=7.0Hz, 1H), 6.74(s, 1H), 7.74(d,     J=9.0Hz, 1H), 8.72(brs1H). 11 BOCNH Et H CHAE S 3410, 2930, 1790,     0.85˜1.95(m, 14H), 1.07(t, J=8Hz, 3H), 1.53(s, 9H), 215˜2.65(     m, (3-7)       1755, 1730, 1680, 4H), 3.20˜3.80(m, 2H), 4.92,     5.00(2Xd, J=5Hz, 1H), 5.82, 5.95(2X       1540, 1290, 1160, dd, J=5Hz,     J=9Hz, 1H), 6.43(t, J=8Hz, 1H), 6.48˜6.58(m, 1H),       1075.     6.73(s, 1H), 6.92, 6.98(2Xq, J=5Hz, 1H), 7.72, 7.74(2Xd, J=9Hz,     1H). 12 BOCNH Et Cl POM SO 3395, 3180br, 1.08(t, J=7.5Hz, 3H), 1.22(s,     9H), 1.52(s, 9H), 2.51(quintet, (3-1), (4-2)       1802, 1753, 1719,     J=7.5Hz, 2H), 3.64, 3.93(ABq, J=16.2Hz, 2H), 4.76(d, 5.0Hz, 1H),     1668, 1547, 1152, 5.89, 6.00(ABq, J=5.4Hz, 2H), 6.19(dd, J=5.0Hz,     J=10.0Hz, 1H),       985. 6.48(t, J=7.5Hz, 1H), 6.73(s, 1H), 8.94(d,     J=10.0Hz, 1H), 8.96        (brs, 1H). 13 BOCNH Et CH.sub.2 OCH.sub.3 POM     S 3420, 2980, 1790, 1.07(t, J=8Hz, 3H), 1.20(s, 9H), 1.53(s, 9H),     2.45(quintet, J= (3-1)       1750, 1730, 1680, 8Hz, 2H), 3.31(s, 3H),     3.53(s, 2H), 4.28(s, 2H), 5.03(d, J=5Hz,       1550, 1375, 1160. 1H),     5.86(s, 2H), 5.90(dd, J=5Hz, J=9Hz, 1H), 6.43(t, J=8Hz,        1H),     6.73(s, 1H), 7.77(d, J=9Hz, 1H), 8.53(brs, 1H). 14 BOCNH Et CH.sub.2     Oi-Pr POM S 3410, 2960, 1780, 1.07(t, J=8Hz, 3H), 1.15(d, J=6Hz, 6H),     1.22(s, 9H), 1.53(s, (3-1)       1750, 1720, 1670, 9H), 2.46(quintet,     J=8Hz, 2H), 3.58(s, 2H), 3.60(septet, J=6Hz,       1540, 1365, 1150,     1H), 4.36(s, 2H), 5.05(d, J=5Hz, 1H), 5.88(s, 2H), 5.90(dd, J=5     1120, 1095 Hz, J=9Hz, 1H), 6.45(t, J=8Hz, 1H), 6.75(s, 1H), 7.80(d,     J=9Hz,        1H). 15 BOCNH Et CH.sub.2 O(2-propenyl) POM S 3410, 1785,     1750, 1.08(t, J=7Hz, 3H), 1.23(s, 9H), 1.53(s, 9H), 2.27˜2.60(m,     2H), (3-1)       1725, 1675. 3.58(s, 2H), 3.97(m, 2H), 4.36(s, 2H),     5.04(d, J=5Hz, 1H), 5.13˜        5.33(m, 2H), 5.67˜6.10(m,     4H), 6.41(t, J=7Hz, 1H), 6.73(s, 1H),        7.64(d, J=8Hz, 1H). 16     BOCNH Et CH.sub.2 O(2-fluoroethyl) POM S 3420, 1792, 1755, 1.07(t,     J=8Hz, 3H), 1.22(s, 9H), 1.52(s, 9H), 2.47(dq, J=8Hz, J= (3-1)     1726, 1678, 1548, 8Hz, 2H), 3.58(s, 2H), 3.68(dt, J=2.5Hz, J=30Hz, 2H),     4.42(s,       1156. 2H), 4.54(dt, J=4.5Hz, J=48Hz, 2H), 5.04(d, J=4.5Hz,     1H), 5.87        (s, 2H), 5.94(dd, J=4.5Hz, J=8Hz, 1H), 6.44(t, J=8Hz,     1H), 6.73        (s, 1H), 7.81(d, J=8Hz, 1H), 8.55(brs, 1H). 17 BOCNH Et     CH.sub.2 OCOMe POM S 3570br, 3415, 1.06(t, J=8.0Hz, 3H), 1.21(s, 9H),     1.53(s, 9H), 2.05(s, 3H), (1-1), (3-1)       3240br, 1790, 2.44(quintet,     J=8.0Hz, 2H), 3.36, 3.55(ABq, J=18.0Hz, 2H), 4.78,       1752, 1730,     1679, 5.07(ABq, J=13.5Hz, 2H), 5.02(d, J=5.0Hz, 1H), 5.86(s, 2H), 5.89         1546, 1159. (dd, J=5.0Hz, J=8.0Hz, 1H), 6.41(t, J=8.0Hz, 1H),     6.71(s, 1H),        7.82(d, J=8.0Hz, 1H), 8.78(brs, 1H). 18 BOCNH Et     CH.sub.2 OCONH.sub.2 AOE S 3520, 3405, 1778, 1.06(t, J=7.5Hz, 3H),     1.46(d, J=6.0Hz, 3H), 1.51(s, 9H), 2.06(s, (3-3)       1722, 1663, 1540,     3H), 2.45(quintet, J=7.5Hz, 2/2H), 2.50(quintet, J=7.5Hz, 2/2H),     1149, 1070. 3.44(brs, 2H), 4.12˜5.31(m, 5H), 5.63˜5.92(m,     1H), 6.38(t, J=7.5        Hz, 1H), 6.72(s, 1H), 6.89(q, J= 6.0Hz, 1/2H),     7.04(q, J=6.0Hz,        1/2H), 7.76(d, J=8.0Hz, 1H). 19 BOCNH Et     CH.sub.2 OCONH.sub.2 POM S   nd 1.07(t, J=7.5Hz, 3H), 1.23(s, 9H),     1.54(s, 9H), 2.47(quintet, J= (1-2), (3-2)        7.5Hz, 2H), 3.40,     3.56(ABq, J=18.0Hz, 2H), 4.79, 5.07(ABq, J=        13.5Hz, 2H), 5.02(d,     J=5.0Hz, 1H), 5.03(s, 2H), 5.87(s, 2H),        5.90(dd, J=5.0Hz,     J=8.5Hz, 1H), 6.41(t, J=7.5Hz, 1H), 6.76(s,        1H), 7.74(d, J=8.5Hz,     1H), 9.11(s, 1H). 20 BOCNH Et CH.sub.2 OCONH.sub.2 POE S 3500, 3410,     2960, 1.07(t, J=8Hz, 3H), 1.20(s, 9H), 1.53(s, 9H),1.46˜1.60(m,     3H), (3-4)       1775, 1730, 1720, 2.25˜2.70(m, 2H), 3.20˜3.8     0(m, 2H), 4.60˜5.30(m, 5H), 5.70˜6.03       1670, 1540,     1150, (m, 1H), 6.43(t, J=8Hz, 1H), 6.76(s, 1H), 6.83˜7.16(m, 1H),          1070. 7.76, 7.81(2Xd, J=9Hz, 1H). 21 BOCNH Et CH.sub.2 OCONH.sub.2     ECE S 3520, 3410, 2960, 1.08(t, J=8Hz, 3H), 1.32(t, J=7Hz, 3H), 1.55(s,     9H), 1.56(d, J=6 (3-5)       1780, 1760, 1730, Hz, 3H), 2.42(quintet,     J=8Hz, 2H), 3.46, 3.62(ABq, J=20Hz, 2H),       1720, 1670, 1540, 4.23(q,     J=7Hz, 2H), 4.86, 5.07(ABq, J=15Hz, 2H), 5.02, 5.08(2Xd,       1370,     1325, 1150, J=5Hz, 1H), 5.53(brs. 2H), 5.87(d, J=5Hz, 1H), 6.43(t,     J=8Hz,       1075. 1H), 6.77(s, 1H), 6.87, 7.00(q, 2X6Hz, 1H). [CDCl.sub.     3 + CD.sub.3 OD] 22 BOCNH Et CH.sub.2 OCONH.sub.2 DOL S 3420, 2980,     1790, 1.07(t, J=8.0Hz, 3H), 1.20(s, 9H), 1.53(s, 9H), 2.45(quintet, J=     (3-6), (5-3)       1750, 1730, 1680, 8.0Hz, 2H), 3.31(s, 3H), 3.53(s,     2H), 4.28(s, 2H), 5.03(d, J=       1550, 1375, 1160. 5Hz, 1H), 5.86(s,     2H), 5.90(dd, J=5Hz, J=9Hz, 1H), 6.43(t, J=8        Hz, 1H), 6.73(s,     1H), 7.77(d, J=9Hz, 1H), 8.53(brs, 1H). 23 BOCNH Et CH.sub.2      S(1,2,3-thiadiazol-5-yl) POM S 3420, 2975, 1795, 1.07(t, J=8Hz, 3H),     1.22(s, 9H), 1.52(s, 9H), 2.48(quintet, J= 8 (3-1)       1750, 1730,     1680, Hz, 2H), 3.53(brs, 2H), 4.00, 4.16(ABq, J=15Hz, 2H), 5.02(d, J=5         1550, 1375, 1160. Hz, 1H), 5.80(s, 2H), 5.86(dd, J=5Hz, J=9Hz, 1H),     6.42(t, J=8Hz,        1H), 6.73(s, 1H), 8.05(d, J=9Hz, 1H), 8.52(s, 1H),     9.22(brs, 1H) 24 BOCNH Et CH.sub.2 S(1,2,3-thiadiazol-5-yl) ECE S   nd     1.08(t, J=7Hz, 3H), 1.31(t, J=7Hz, 3H), 1.52(s, 9H), 1.53(d, J=6 (5-1)          Hz, 3H), 2.43(quintet, J=7Hz, 2H), 3.62(s, 2H), 4.02, 4.27(ABq,        J=13Hz, 2H), 4.25(q, J=7Hz, 2H), 5.09(d, J=5Hz, 1H), 5.86(d, J=5       Hz, 1H), 6.43(t, J=7Hz, 1H), 6.78(s, 1H), 6.85(q, J=6Hz, 1H),     8.56(s, 1H). [CDCl.sub.3 + CD.sub.3 OD] 25 BOCNH Et CH.sub.2      S(2-Me1,3,4-thiadiazol-5-yl) POM S 3420, 2970, 1785, 1.07(t, J=8Hz,     3H), 1.20(s, 9H), 1.50(s, 9H), 2.49(quintet, J=8 (3-1)       1750, 1725,     1675, Hz, 2H), 2.72(s, 3H), 3.72(s, 2H), 4.24, 4.60(ABq, J=14Hz, 2H),        1540, 1375, 1160. 5.03(d, J=5Hz, 1H), 5.89, 5.96(ABq, J=6Hz, 2H),     5.92(dd, J=5Hz,        J=8Hz, 1H), 6.43(t, J=8Hz, 1H), 6.76(s, 1H),     7.82(d, J=8Hz, 1H),        8.53(brs, 1H). 26 BOCNH Et CH.sub.2      S(2-H.sub.2 N1,3,4-thiadiazol-5-yl) POM S 3400, 2960, 1780, 1.06(t,     J=8Hz, 3H), 1.20(s, 9H), 1.50(s, 9H), 2.49(quintet, J=8 (3-1)     1750, 1720, 1670, Hz, 2H), 3.64(s, 2H), 4.16(brs, 2H), 5.02(d, J=5Hz,     1H), 5.63       1600, 1540, 1370, (brs, 2H), 5.83, 5.90(ABq, J=6Hz, 2H),     5.90(dd, J=5Hz, J=9Hz,       1150. 1H), 6.40(t, J=8Hz, 1H), 6.75(s, 1H),     8.06(d, J=9Hz, 1H), 9.25        (brs, 1H). 27 BOCNH Et CH.sub.2      S(1-HOCH.sub.2 CH.sub.2tetrazol-5-yl) POM S 3420, 2980, 1790, 1.06(t,     J=8Hz, 3H), 1.20(s, 9H), 1.50(s, 9H), 2.50(quintet, J=8 (3-1)     1750, 1730, 1675, Hz, 2H), 3.70(s, 2H), 3.95˜4.15(m, 2H), 4.20.abou     t.4.45(m, 4H), 5.03       1540, 1375, 1160, (d, J=5Hz, 1H), 5.88(s, 2H),     5.86(dd, J=9Hz, J=5Hz, 1H), 6.40        (t, J=8Hz, 1H), 6.77(s, 1H),     7.95(d, J=9Hz, 1H), 9.00(brs, 1H). 28 BOCNH n-Pr H POM S 3500, 3400,     3200, 0.96(t, J=7Hz, 3H), 1.22(s, 9H), 1.53(s, 9H), 1.40˜1.63(m,     2H), (3-1)       1785, 1750, 1720, 2.40(brq, J=7Hz, 2H), 3.23˜3.77(     m, 2H), 5.02(d, J=5Hz, 1H),       1665, 1640. 5.82, 5.90(ABq, J=6Hz,     2H), 5.97(dd, J=8Hz, J=5Hz, 1H), 6.43(t,        J=8Hz, 1H), 6.52˜6.     63(m, 1H), 6.75(s, 1H), 7.50(d, J=8Hz, 1H). 29 BOCNH i-Pr H POM S 3500,     3400, 3220, 1.07(d, J=7Hz, 6H), 1.20(s, 9H), 1.53(s, 9H), 2.71˜3.18     (m, 1H), (3-1)       1785, 1745, 1720, 3.27˜3.80(m, 2H), 5.03(d,     J=5Hz, 1H), 5.83, 5.92(ABq, J=5Hz,       1675, 1635. 2H), 5.97(dd,     J=8Hz, J=5Hz, 1H), 6.30(d, J=11Hz, 1H), 6.53˜6.65        (m, 1H),     6.79(s, 1H), 7.67(d, J=8Hz, 1H), 8.33(brs, 2H). 30 BOCNH cyc-Pr H POM S     3415, 1788, 1750, 0.5˜1.02(m, 4H), 1.22(s, 9H), 1.53(s, 9H),     2.10˜2.45(m, 1H), (3-1)       1726, 1670, 1545, 3.42(dd, J=5.4Hz,     J=18Hz, (A of ABX), 1H), 3.61(dd, J=2.7Hz, J=       1157. 18Hz, (B of     ABX), 1H), 5.02(d, J=5Hz, 1H), 5.78(d, J=12Hz, 1H),        5.80,     5.89(ABq, J=5Hz, 2H), 5.99(dd, J=5Hz, J=8.5Hz, 1H), 6.55        (dd,     J=2.7Hz, J=5.4Hz, (X of ABX), 1H), 7.79(d, J=8.5Hz, 1H). 31 BOCNH     cyc-PrMe H POM S   nd 0.03˜1.3(m, 5H), 1.20(s, 9H), 1.51(s, 9H),     2.34(dd, J=7.5Hz, J= (3-1)        7.5Hz, 2H), 3.39(dd, J=5.5Hz, J=19.8Hz,      (A of ABX), 1H), 3.57        (dd, J=3.6Hz, J=19.8Hz, (B of ABX), 1H),     4.98(d, J=5Hz, 1H),        5.80, 5.87(ABq, J=4.5Hz, 2H), 5.91(dd, J=5Hz,     J=8.5Hz, 1H), 6.52        (t, J=7.5Hz, 1H), 6.53(dd, J=3.6Hz, J=5.5Hz,     (X of ABX), 1H),        6.75(s, 1H), 7.76(d, J=8.5Hz, 1H), 8.70(brs,     1H). 32 BOCNH t-Bu H POM S 3415, 1793, 1750, 1.17(s, 9H), 1.21(s, 9H),     1.52(s, 9H), 3.38(dd, A of ABX, J=6.0 (3-1)       1726, 1682, 1545, Hz,     J=18.5Hz, 1H), 3.57(dd, B of ABX, J=3.0Hz, J=18.5Hz, 1H),       1157,     1003. 5.0(d, J=5.0Hz, 1H), 5.81, 5.90(ABq, J=5.5Hz, 2H), 6.0(dd, J=       5.0Hz, J=9.0Hz, 1H), 6.41(s, 1H), 6.56(dd. X of ABX, J=3.0Hz,     J=6.0Hz, 1H), 6.70(s, 1H), 7.76(d, J=9.0Hz, 1H), 8.83(brs, 1H). 33 BOCNH     cyc-Pn CH.sub.2 OCONH.sub.2 POM S 3520, 3410, 1782, 1.22(s, 9H), 1.53(s,     9H), 1.30˜2.0(m, 8H), 2.85˜3.16(m, 1H), (3-1)       1740,     1724, 1670, 3.44(ABq, J=18.5Hz, 2H), 4.81, 5.07(ABq, J=13.5Hz, 2H),     5.04(d,       1539, 1150. J=5Hz, 1H), 5.28(brs, 2H), 5.87, 5.94(ABq,     J=5.8Hz, 2H), 5.92        (dd, J=5Hz, J=7.5Hz, 1H), 6.35(d, J=10Hz, 1H),     6.77(s, 1H), 7.64        (d, J=7.5Hz, 1H). 34 BOCNH cyc-PnMe H POM S     3415, 1787, 1750, 1.21(s, 9H), 1.30˜1.88(m, 9H), 1.52(s, 9H),     2.48(dd, J=8Hz, 2H), (3-1)       1723, 1674, 1542, 3.42(dd, J=6Hz,     J=19Hz, (A of ABX), 1H), 3.61(dd, J=3.6Hz, J=19       1155. Hz, (B of     ABX), 1H), 5.03(d, J=4.5Hz, 1H), 5.84, 5.92(ABq, J=4.5        Hz, 2H),     5.96(dd, J=4.5Hz, J=8.5Hz, 1H), 6.49(t, J=8Hz, 1H),        6.60(dd,     J=3.6Hz, J=6Hz, (X of ABX), 1H), 6.77(s, 1H), 7.64(d,        J=8.5Hz,     1H), 8.48(brs, 1H). 35 BOCNH MeOMe CH.sub.2 OCONH.sub.2 POM S 3517,     3418, 3183, 1.23(s, 9H), 1.52(s, 9H), 3.37(s, 3H), 3.35, 3.57(ABq,     J=18Hz, (3-1)       1784, 1728, 1676, 2H), 4.43(d, J=5.5Hz, 2H), 4.77,     5.04(ABq, J=14Hz, 2H), 4.98(d,       1622, 1327, 1298, J=4.5Hz, 1H),     5.10(brs, 2H), 5.78(dd, J=4.5Hz, J=8Hz, 1H), 5.85       1154, 1121,     1093, (s, 2H), 6.57(t, J=5.5Hz, 1H), x6.92(s, 1H), 8.34(d, J=8Hz, 1H).         1072, 999, 981. 36 CbzNH Et H POM S 3410, 3240br, 1.03(t, J=7.5Hz,     3H), 1.20(s, 9H), 2.38(quintet, J=7.5Hz, 2H), (3-1)       1790, 1750,     1738, 3.30(dd, A of ABX, J=6Hz, J=18.9Hz, 1H), 3.51(dd, B of ABX, J=3        1678, 1552, 1290, Hz, J=18.9Hz, 1H), 4.98(d, J=5.5Hz, 1H), 5.15,     5.30(ABq, J=13.0       1130, 1095. Hz, 2H), 5.78, 5.85(Abq, J=4.5Hz,     2H), 5.92(dd, J=5.5Hz, J=8Hz,        1H), 6.43(t, J=7.5Hz, 1H), 6.70(s,     1H), 7.36(s, 5H), 7.89(d, J=8        Hz, 1H), 9.45(brs, 1H). 37 OHCNH Et     H POM S 2970, 1790, 1755, 1.07(t, J=8Hz, 3H), 1.20(s, 9H), 2.37(quintet,     J=8Hz, 2H), 3.20˜ (7-1)       1705, 1680, 1550, 3.76(m, 2H),     4.97(d, J=5Hz, 1H), 5.82(s, 2H), 5.92(dd, J=5Hz, J=       1290, 1130.     9Hz, 1H), 6.45(t, J=8Hz, 1H), 6.50˜6.62(m, 1H), 6.77(s, 1H),      7.93(d, J=9Hz, 1H), 8.49(s, 1H). 38 ClCH.sub.2 CONH Et H POM S 3500,     3370, 3230, 1.08(t, J=8Hz, 3H), 2.25˜2.63(m, 2H), 3.23˜3.78(m     , 2H), 4.27(s, (7-1)       1790, 1755, 1685, 2H), 5.02(d, J=5Hz, 1H),     5.86(s, 2H), 5.90(dd, J=8Hz, J=5Hz,       1640. 1H), 6.47(t, J=9Hz, 1H),     6.55˜6.61(m, 1H), 6.85(s, 1H), 7.78(d,        J=8Hz, 1H). 39     NO.sub.2 PhCHN Et H POM S 3410, 1785, 1745, 1.14(t, J=7Hz, 3H), 1.22(s,     9H), 2.56(q, J=7Hz, 2H), 3.23˜3.82 (7-1)       1675, 1635, 1520,     (m, 2H), 5.08(d, J=5Hz, 1H), 5.87, 5.97(ABq, J=5Hz, 2H), 6.03     1345. (dd, J=5Hz, J=8Hz, 1H), 6.57˜6.69(m, 1H), 6.69(t, J=7Hz,     1H),        7.27(s, 1H), 7.71(d, J=8Hz, 1H), 8.16, 8.34(ABq, J=9Hz, 4H),            9.21(s, 1H).

    TABLE 3      Synthesis of Pharmaceutical esters      ##STR7##              Start. Mat. Solvent   Time Temp Yld. Crop No. R R.sup.1 R.sup.2     R.sup.3 X Ex. No. (mg) (ml) Reagent Subreagent (hr) (°C.) (%)     (mg)   1 H.sub.2 N Me H POM S (2-1) R = BOCNH 100 -- TFA 1 ml  1 rt 85     70       (2-4) R = BOCNH 150 DCM 1 AlCl.sub.3 51 mg 1.5 eq. anisole 0.5     ml 0.1 -30 74 92  2 H.sub.2 N Me CH.sub.2 OCONH.sub.2 POM S (2-5) R =     BOCNH 160 -- TFA 2 ml  2 rt 55 75  3 H.sub.2 N Me CH.sub.2      S(1,2,3-thiadiazol-5-yl) POM S (2-1) R = BOCNH 102 -- TFA 2 ml  0.8 rt     55 48  4 H.sub.2 N Et H AOM S (2-1) R = BOCNH 163 -- TFA 3 ml  1 rt 87     116   5 H.sub.2 N Et H AOE S (2-1) R = BOCNH 90 -- TFA 1.5 ml  1 rt 59     45       (3-3) R.sup.3 = H 95 DMF 1 AOEBr 165 μl K.sub.2 CO.sub.3 110     mg 2.5 -30˜0 33 38  6 H.sub.2 N Et H POM S (2-1) R = BOCNH 480 --     TFA 5 ml  1 rt 87 340        (2-2) R = ClCH.sub.2 CONH THF 2 NH.sub.2     CSNH.sub.2 AcONa 41 mg 2 eq. 4 rt 80 99        143  76 mg 4 eq MeOH 2 ml           (2-3) R = HCONH 183 HOAc 2 NHCl 0.3 ml  3.5 rt 63 110        (2-4)     R = BOCNH 120 DCM 1 AlCl.sub.3 80 mg 3 eq anisole 0.5 ml 0.1 -30 81 80         (3-1) R.sup.3 = H 114 DMF 1.5 POMl 56 μl 1.1 eq K.sub.2 CO.sub.3     62 mg 2 eq 0.5 -30 33 49       (5-2) X = SO 100 DCM 4 PBr.sub.3 40 μl     2 eq  0.8 -30 66 78  7 H.sub.2 N HCl Et H POM S (6-2) R = NH.sub.2 82     DCM 1 HCl/EtOAc then rinsed with Et.sub.2 O -- -- 87 63  8 H.sub.2 N Et     H POE S (2-1) R = BOCNH 160 -- TFA 3 ml  1 rt 47 63  9 H.sub.2 N Et H     ECE S (2-1) R = BOCNH 189 -- TFA 3.5 ml  1 rt 76 119  10 H.sub.2 N Et H     DOL S (2-1) R = BOCNH 83 -- TFA 1 ml  1.5 rt 62 43 11 H.sub.2 N Et H     CHAE S (2-1) R = BOCNH 150 -- TFA 3 ml  1 rt 69 88 12 H.sub.2 N Et Cl     POM S (2-1) R = BOCNH 130 -- TFA 1.5 ml  2 rt 64 70       (5-2) X = SO     51 DCM 2 PBr.sub.3 19 μl  1 -30 83 41 13 H.sub.2 N Et Cl POM SO (2-1)     R = BOCNH 130 -- TFA 1 ml  2.5 rt 25 28 14 H.sub.2 N Et CH.sub.2     OCH.sub.3 POM S (2-1) R = BOCNH 173 -- TFA 3.5 ml  1 rt 90 131     (2-5) R = BOCNH 173 DCM 1.5 AlCl.sub.3 72 mg 2 eq anisole 1 0.2 -30 86     125  15 H.sub.2 N Et CH.sub.2 Oi-Pr POM S (2-1) R = BOCNH 150 -- TFA 3     ml  1 rt 33 42 16 H.sub.2 N Et CH.sub.2 O(2-propenyl) POM S (2-1) R =     BOCNH 128 -- TFA 1 ml anisole 0.3 ml 1 rt 47 80 17 H.sub.2 N Et CH.sub.2     O(2-fluoroethyl) POM S (2-1) R = BOCNH 150 DCM 0.7 TFA 0.33 ml anisole     0.25 ml 2.5 rt 87 110  18 H.sub.2 N Et CH.sub.2 OCOMe POM S (2-1) R =     BOCNH 123 -- TFA 1 ml  2 rt 52 54 19 H.sub.2 N Et CH.sub.2 OCONH.sub.2     AOE S (2-1) R = BOCNH 80 -- TFA 0.6 ml  1 rt 64 43 20 H.sub.2 N Et     CH.sub.2 OCONH.sub.2 POM S (2-1) R = BOCNH 450 -- TFA 5 ml  2 rt 76 290     21 H.sub.3 N.sup.+CF.sub.3 COO Et CH.sub.2 OCONH.sub.2 POM S (6-1) R =     NH.sub.2 290 DCM 4 TFA 1 then rinsed with Et.sub.2 O -- -- 83 290  22     H.sub.2 N Et CH.sub.2 OCONH.sub.2 POE S (2-1) R = BOCNH 102 --  TFA 2 ml      0.8 rt 48 42 23 H.sub.2 N Et CH.sub.2 OCONH.sub.2 ECE S (2-1) R = BOCNH     165 -- TFA 3.5 ml  1 rt 50 70 24 H.sub.2 N Et CH.sub.2 OCONH.sub.2 DOL S     (2-1) R = BOCNH 110 -- TFA 1 ml  2.5 rt 27 25       (2-4) R = BOCNH 110     DCM 1 TiCl.sub.4 38 μl 2 eq anisole 1 ml 0.3 -30 74 69 25 H.sub.2 N     Et CH.sub.2 S(1,2,3-thiadiazol-5-yl) POM S (2-1) R = BOCNH 105 -- TFA 2     ml   7/6 rt 92 84 26 H.sub.2 N Et CH.sub.2 S(1,2,3-thiadiazol-5-yl) ECE     S (2-1) R = BOCNH 105 -- TFA 2 ml  0.7 rt 43 39 27 H.sub.2 N Et CH.sub.2     S(2-Me1,3,4- POM S (2-1) R = BOCNH 186 -- TFA 3.7 ml  11/6 rt 85 136     thiadiazol-5-yl) 28 H.sub.2 N Et CH.sub.2 S(2-H.sub.2 N1,3,4- POM S     (2-1) R = BOCNH 128 -- TFA 2.5 ml  2 rt 88 98    thiadiazol-5-yl) 29     H.sub.2 N Et CH.sub.2 S(1- POM S (2-1) R = BOCNH 181 -- TFA 3.7 ml  2 rt     60 94    HOCH.sub.2 CH.sub.2tetrazol-5-yl) 30 H.sub.2 N n-Pr H POM S     (2-1) R = BOCNH 201 -- TFA 1 ml  3 rt 60 100  31 H.sub.2 N i-Pr H POM S     (2-1) R = BOCNH 186 -- TFA 1 ml  3 rt 70 108  32 H.sub.2 N cyc-Pr H POM     S (2-1) R = BOCNH 133 -- TFA 2.6 ml  1 rt 59 65 33 H.sub.2 N t-Bu H POM     S (2-1) R = BOCNH 53 -- TFA 1 ml  2 rt 90 40       (2-4) R = BOCNH 106     DCM 1 SnCl.sub.4 40 μl 2 eq anisole 1 1 -10 85 75 34 H.sub.2 N     cyc-PrMe H POM S (2-1) R = BOCNH 64 -- TFA 1 ml  2 rt 65 35 35 H.sub.2 N     cyc-Pn H POM S (3-1) R.sup.3 = H 102 DMF 2 POMl 50 μl 1.2 eq K.sub.2     CO.sub.3 67 mg 1 -25 53 69 36 H.sub.2 N cyc-PnMe H POM S (2-1) R = BOCNH     105 -- TFA 2 ml  0.7 rt 91 80 37 H.sub.2 N cyc-Pn CH.sub.2 OCONH.sub.2     POM S (2-1) R = BOCNH 210 -- TFA 2 ml  2.5 rt 76 127  38 H.sub.2 N MeOMe     CH.sub.2 OCONH.sub.2 POM S (2-1) R = BOCNH 198 DCM 2 TFA 500 μl  6.3     rt 62 108

    TABLE 4      Synthesis of protected pharmaceutical esters      ##STR8##            Start. Mat. Solvent   Time Temp Yld. Crop No. R R.sup.1 R.sup.2     R.sup.3 X Ex. No. (mg) (ml) Reagent Subreagent (hr) (°C.) (%)     (mg)   1 BOCNH Me H POM S (3-1) R.sup.3 = H 100 DMF 1 POMI 45 μl     K.sub.2 CO.sub.3 45 mg 0.5 -30 80 100       (1-3) H.sub.2 NQ" 157 DCM 10     Q'COOH 142 mg, picoline 98 μl 2 eq 0.5 -40 56 162          (COCI).sub.     2 42.6 μl 1 eq  2 BOCNH Me CH.sub.2 OCONH.sub.2 POM S (3-1) R.sup.3 =     H 216 DMF 4 POMI 78 μl K.sub.2 CO.sub.3 110 mg 0.7 -20 57 150  3     BOCNH Me CH.sub.2 S(1,2,3-thiadiazol-5-yl) POM S (3-1) R.sup.3 = H 234     DMF 2.3 POMI 100 μl K.sub.2 CO.sub.3 152 mg 0.5 -25˜-30 37 104     4 BOCNH Et H AOM S (3-2) R.sup.3 = H 240 DMF 2.4 AOMBr 115 mg K.sub.2     CO.sub.3 138 mg 0.7 0 48 132  5 BOCNH Et H AOE S (1-4) H.sub.2 NQ" 161     DCM 8 Q'COOH 149 mg. NEt.sub.3 83 μl 3 -60 83 235          MeSO.sub.2     Cl 40 μl Memorpholine 132 μ1       (3-3) R.sup.3 = H 170 DMF 2     AOEBr 230 μl K.sub.2 CO.sub.3 152 mg. Kl 300 mg 1.5 - 20 32  65  6     BOCNH Et H POM S (3-1) R.sup.3 = H 572 DMF 8 POMl 223 μl K.sub.2     CO.sub.3 329 mg 1 -30 68 485       (5-1) X = SO 61 DCM 2 PBr.sub.3 19.3     μl 2 eq  0.5 -30 86  51  7 BOCNH Et H POM SO (3-1) R.sup.3 = H 175     DMF 3.5 POMl 68 μl K.sub.2 CO.sub.3 97.5 mg 2 -20 48 103       (4-1)     X = S 300 DCM 8 m-CPBA 108 mg   0.25 rt 90 275  8 BOCNH Et H POE S (3-4)     R.sup.3 = H 240 DMF 2.4 POEl 460 μl, K.sub.2 CO.sub.3 138 mg 1     -25˜-30 53 161          POECl 320 μl  9 BOCNH Et H ECE S (3-5)     R.sup.3 = H 240 DMF 2.4 ECEBr 150 mg 1.5 eq K.sub.2 CO.sub.3 138 mg 0.5     - 10 64 191 10 BOCNH Et H DOL S (3-6) R.sup.3 = H 144 DMF 4 DOLBr 102 mg     1.5 eq K.sub.2 CO.sub.3 83 mg 0.5 0 47  83 11 BOCNH Et H CHAE S (3-7)     R.sup.3 = H 240 DMF 2.4 CHAEl 355 mg K.sub.2 CO.sub.3 138 mg 0.8 -30 47     152 12 BOCNH Et Cl POM SO (3-1) R.sup.3 = H 106 DMF 2 POMl 38 μl 1.1     eq K.sub.2 CO.sub.3 55 mg 0.7 -30 58  75       (4-2) X = S 410 DCM 4     m-CPBA 47.4 mg  0.3 0 30 135 13 BOCNH Et CH.sub.2 OCH.sub.3 POM S (3-1)     R.sup.3 = H 159 DMF 1.5 POMl 77 μl K.sub.2 CO.sub.3 84 mg 1 -30 90     173 14 BOCNH Et CH.sub.2 Oi-Pr POM S (3-1) R.sup.3 = H 120 DMF 1.2 POMl     55 μl K.sub.2 CO.sub.3 152 mg 1 -30 97 140 15 BOCNH Et CH.sub.2     O(2-propenyl) POM S (3-1) R.sup.3 = H 193 DMF 3 POMl 120 μl 2 eq     K.sub.2 CO.sub.3 97 mg 2 -40 55 128 16 BOCNH Et CH.sub.2      O(2-fluoroethyl) POM S (3-1) R.sup.3 = H 175 DMF 2 POMl 64 μl 1.2 eq     K.sub.2 CO.sub.3 87 mg 0.5 -35 81 170 17 BOCNH Et CH.sub.2 OCOMe POM S     (1-1) H.sub.2 NQ" 193 DCM 2 Q'COOH 164 mg 1.1 eq. pyridine 162 μl 4     eq 1.5 -15 48 160          cyanuric Cl 194 mg 1.1 eq       (3-1) R.sup.3     = H 123 DMF 2 POMl 43 μl K.sub.2 CO.sub.3 62 mg 1 -30 84 123 18 BOCNH     Et CH.sub.2 OCONH.sub.2 AOE S (3-3) R.sup.3 = H 166 DMF 3 AOEBr 43 μl     1.2 eq K.sub.2 CO.sub.3 83 mg 3 0 36  70 19 BOCNH Et CH.sub.2      OCONH.sub.2 POM S (1-2) H.sub.2 NQ" 194 DCM 1 Q'COOH 149 mg 1 eq     NEt.sub.3 125 μl, POCl.sub.3 52 μl 1  -5 54 180       (3-1)     R.sup.3 = H 673 DMF 8 POMl 220 μl K.sub.2 CO.sub.3 318 mg 1.5 -30 74     570 20 BOCNH Et CH.sub.2 OCONH.sub.2 POE S (3-4) R.sup.3 = H 186 DMF 2     POMl 120 μl K.sub.2 CO.sub.3 93 mg 2 -10˜-30 45 104 21 BOCNH Et     CH.sub.2 OCONH.sub.2 ECE S (3-5) R.sup.3 = H 254 DMF 2.5 ECEBr 272 μl     K.sub.2 CO.sub.3 127 mg 1.5 0 54 166 22 BOCNH Et CH.sub.2 OCONH.sub.2     DOL S (5-3) X = SO 160 DCM 15 PBr.sub.3 65 μl 3 eq  1 -30 72 110      (3-6) R.sup.3 = H 123 DMF 3 DOLBr 75 mg 1.5 eq K.sub.2 CO.sub.3 61 mg     0.7 0 64  94 23 BOCNH Et CH.sub.2 S(1,2,3-thiadiazol-5-yl) POM S (3-1)     R.sup.3 = H 310 DMF 3 POMl 130 μl K.sub.2 CO.sub.3 140 mg 5/6 -25 29     107 24 BOCNH Et CH.sub.2 S(1,2,3-thiadiazol-5-yl) ECE S (5-1) X = SO 170     DCM 4 PBr.sub.3 55 μl 2 eq  0.5 -25 63 105 25 BOCNH Et CH.sub.2       1     S(2-Me,3,4- POM S (3-1) R.sup.3 = H 279 DMF 5 POMl 150 μl K.sub.2     CO.sub.3 93 mg 1 -25˜-30 56 186    thiadiazol-5-yl) 26 BOCNH Et     CH.sub.2 S(2-H.sub.2 N1,3,4- POM S 3-1) R.sup.3 = H 195 DMF 3 POMl 63     μl K.sub.2 CO.sub.3 86 mg 1 -15˜-30 55 128    thiadiazol-5-yl)     27 BOCNH Et CH.sub.2 S(1- POM S (3-1) R.sup.3 = H 279 DMF 3 POMl 112     μl K.sub.2 CO.sub.3 122 mg 1 -15˜-30 55 183    HOCH.sub.2     CH.sub.2tetrazol-5-yl 28 BOCNH n-Pr H POM S (3-1) R.sup.3 = H 289 DMF 4     POMl 200 μl K.sub.2 CO.sub.3 163 mg 1 -20 70 201 29 BOCNH i-Pr H POM     S (3-1) R.sup.3 = H 259 DMF 4 POMl 170 μl K.sub.2 CO.sub.3 138 mg 2/3     -30 63 186 30 BOCNH cyc-Pr H POM S (3-1) R.sup.3 = H 312 DMF 3 POMl 118     μl 1.2 eq K.sub.2 CO.sub.3 128 mg 1.5 -30 47 133 31 BOCNH cyc-PrMe H     POM S (3-1) R.sup.3 = H 150 DMF 2 POMl 61 μl 1.2 eq K.sub.2 CO.sub.3     60 mg 0.5 -30 34  64 32 BOCNH t-Bu H POM S (3-1) R.sup.3 = H 120 DMF 2     POMl 43 μl K.sub.2 CO.sub.3 61 mg 1 -30 31  43 33 BOCNH cyc-PnMe H     POM S (3-1) R.sup.3 = H 230 DMF 3 POMl 87 μl 1.2 eq K.sub.2 CO.sub.3     89 mg 0.7 -30 38 105 34 BOCNH cyc-Pn CH.sub.2 OCONH.sub.2 POM S (3-1)     R.sup.3 = H 236 DMF 3 POMl 78 μl 1.2 eq K.sub.2 CO.sub.3 107 mg 1 -25     79 216 35 BOCNH MeOMe CH.sub.2 OCONH.sub.2 POM S (3-1) R.sup.3 = H 371     DMA 5 POMl 120 μl 1.2 μl K ethylhexanoate 0.54 ml 1.5  -7 43 195     36 CbzNH Et H POM S (3-1) R.sup.3 = H 153 DMF 3 POMl 65 μl K.sub.2     CO.sub.3 92 mg 0.5 -20 72 136 37 OHCNH Et H POM S (7-1) R = H.sub.2 N 50     -- HCOOH 26 μl Ac.sub.2 O 66 μl 0.5 rt 90  47 38 ClCH.sub.2 Et H     POM S (7-1) R = H.sub.2 N 50 DCM 1 ClCH.sub.2 COCl 12 μl pyridine 12     μl 0.5 -20 95  54  CONH 39 NO.sub.2 Et H POM S (7-1) R = H.sub.2 N 50     DCM 3 O.sub.2 NC.sub.6 H.sub.4 CHO 23 mg MeC.sub.6 H.sub.4 SO.sub.3 H 1     mg 2.5  45 32     (Abbreviations)     Q" = cephem nucleus     Q' = side chain acid minus carboxy

What we claim is:
 1. A 7β-[2-(2-amino-4-thiazolyl)alkenoylamino]-3-cephem-4-carboxylic acid pharmaceutically acceptable ester represented by the following formula: ##STR9## wherein R is amino, X is sulfur, andR¹ is ethyl; R² is CH₂ OCH₂ CH═CH₂ ; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is CH₂ OCH₂ CH₂ F; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is CH₂ OMe; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is CH₂ OCH(Me)₂ ; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is H; and R³ is pivaloyloxymethyl; R¹ is methyl; R² is CH₂ OCONH₂ ; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is CH₂ OCONH₂ ; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is H; and R³ is 1-ethoxycarbonyloxyethyl; R¹ is ethyl; R² is H; and R³ is pivaloyloxyethyl; R¹ is ethyl; R² is H; and R³ is acetoxyethyl; R¹ is ethyl; R² is H; and R³ is acetoxymethyl; R¹ is methyl; R² is H; and R³ is pivaloyloxymethyl; R¹ is ethyl; R² is CH₂ OCONH₂ ; and R³ is acetoxyethyl; R¹ is ethyl; R² is CH₂ OCONH₂ and R³ is 1-ethoxycarbonyloxyethyl; or R¹ is cycloproplymethyl; R² is H; and R³ is pivaloyloxymethyl.
 2. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OCH₂ CH═CH₂ ; and R³ is pivaloyloxymethyl.
 3. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OCH₂ CH₂ F; and R³ is pivaloyloxymethyl.
 4. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OMe; and R³ is pivaloyloxymethyl.
 5. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OCH(Me)₂ ; and R³ is pivaloyloxymethyl.
 6. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is H; and R³ is pivaloyloxymethyl.
 7. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is methyl; R² is CH₂ OCONH₂ ; and R³ is pivaloyloxymethyl.
 8. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OCONH₂ ; and R³ is pivaloyloxymethyl.
 9. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is H; and R³ is -ethoxycarbonyloxyethyl.
 10. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is H; and R³ is pivaloyloxyethyl.
 11. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is H; and R³ is acetoxyethyl.
 12. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is H; and R³ is acetoxymethyl.
 13. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is methyl; R² is H; and R³ is pivaloyloxymethyl.
 14. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OCONH₂ ; and R³ is acetoxyethyl.
 15. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is ethyl; R² is CH₂ OCONH₂ and R³ is 1-ethoxycarbonyloxyethyl.
 16. The compound as claimed in claim 1 wherein R is amino; X is sulfur; R¹ is cyclopropylmethyl; R² is H; and R³ is pivaloyloxymethyl.
 17. An oral antibacterial preparation containing an antibacterially effective amount of a compound claimed in claim
 1. 